Compositions comprising an aryl pyrazole and/or a formamidine, methods and uses thereof

ABSTRACT

This invention relates to compositions for combating parasites in animals, comprising 1-arylpyrazole compounds alone or in combination with formamidine compounds. This invention also provides for an improved methods for eradicating, controlling, and preventing parasite infestation in an animal comprising administering the compositions of the invention to the animal in need thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 12/618,534 filed on Nov. 13, 2009; which claims thebenefit of priority to U.S. Provisional Application Nos. 61/116,038,filed Nov. 19, 2008; 61/142,561, filed Jan. 5, 2009; and 61/167,381,filed Apr. 7, 2009; the disclosures of which are all incorporated hereinby reference in their entirety.

INCORPORATION BY REFERENCE

Any foregoing applications, and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.Reference is made to U.S. Patent Publication Nos. US 2005/0234119 toSoll et al.; US 2008/0003282 to Soll et al.; US 2008/0031902 to Lee etal.; and U.S. Pat. No. 7,531,186, which issued on May 12, 2009, all ofwhich are incorporated by reference herein in their entirety.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

FIELD OF THE INVENTION

The present invention provides veterinary compositions comprising1-arylpyrazoles, alone or in combination with other active agents, foreradicating ectoparasites and/or endoparasites; the use of thesecompositions against ectoparasites and/or endoparasites, and methods forpreventing or treating parasitic infestations of animals comprisingadministering the inventive composition of the invention to the animal.Also provided are compositions comprising a formamidine that exhibitimproved stability, and a kit for treating or preventing parasiticinfestations in animals, which comprises at least one 1-arylpyrazolesand at least one formamidines in a dual-cavity container.

BACKGROUND OF THE INVENTION

Animals such as mammals and birds are often susceptible to parasiteinfestations/infections. These parasites may be ectoparasites, such asinsects, and endoparasites such as filariae and other worms.Domesticated animals, such as cats and dogs, are often infested with oneor more of the following ectoparasites:

-   -   fleas (Ctenocephalides spp., such as Ctenocephalides felis and        the like),    -   ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp.,        Amblyoma spp., and the like),    -   mites (Demodex spp., Sarcoptes spp., Otodectes spp., and the        like),    -   lice (Trichodectes spp., Cheyletiella spp., Lignonathus spp. and        the like),    -   mosquitoes (Aedes spp., Culux spp., Anopheles spp. and the like)        and    -   flies (Hematobia spp., Musca spp., Stomoxys spp., Dematobia        spp., Coclyomia spp. and the like).

Fleas are a particular problem because not only do they adversely affectthe health of the animal or human, but they also cause a great deal ofpsychological stress. Moreover, fleas are also vectors of pathogenicagents in animals, such as dog tapeworm (Dipylidium caninum), andhumans.

Similarly, ticks are also harmful to the physical and psychologicalhealth of the animal or human. However, the most serious problemassociated with ticks is that they are the vector of pathogenic agentsin both humans and animals. Major diseases which are caused by ticksinclude borrelioses (Lyme disease caused by Borrelia burgdorferi),babesioses (or piroplasmoses caused by Babesia spp.) and rickettsioses(also known as Rocky Mountain spotted fever). Ticks also release toxinswhich cause inflammation or paralysis in the host. Occasionally, thesetoxins are fatal to the host.

Moreover, mites and lice are particularly difficult to combat sincethere are very few active substances which act on these parasites andthey require frequent treatment.

Likewise, farm animals are also susceptible to parasite infestations.For example, cattle are affected by a large number of parasites. Aparasite which is very prevalent among farm animals is the tick genusBoophilus, especially those of the species microplus (cattle tick),decoloratus and annulatus. Ticks, such as Boophilus microplus, areparticularly difficult to control because they live in the pasture wherefarm animals graze. Other important parasites of cattle and sheep arelisted as follows:

-   -   myiases-causing flies such as Dermatobia hominis (known as Berne        in Brazil) and Cochlyomia hominivorax (greenbottle); sheep        myiases-causing flies such as Lucilia sericata, Lucilia cuprina        (known as blowfly strike in Australia, New Zealand and South        Africa). These are flies whose larva constitutes the animal        parasite;    -   flies proper, namely those whose adult constitutes the parasite,        such as Haematobia irritans (horn fly);    -   lice such as Linognathus vitulorum, etc.; and    -   mites such as Sarcoptes scabiei and Psoroptes ovis.

1-arylpyrazoles as a class of chemicals are well known in the art, andcertain compounds in this class have been found to be potently activeagainst a wide range of pests and parasites that are harmful to animalsand plants. For example, 1-arylpyrazole derivatives are known in the artto prevent, treat or control ectoparasitic infestations in mammals, suchas cats, dogs and cattle. Certain 1-arylpyrazoles and their use againstpests are described in US Patent Publication Nos. US 2005/0182048; US2006/0135778; US 2008/0132487; US 2008/0031902; U.S. Pat. Nos.4,963,575; 5,122,530; 5,232,940; 5,236,938; 5,246,255; 5,547,974;5,567,429; 5,576,429; 5,608,077; 5,714,191; 5,814,652; 5,885,607;5,567,429; 5,817,688; 5,885,607; 5,916,618; 5,922,885; 5,994,386;6,001,384; 6,010,710; 6,057,355; 6,069,157; 6,083,519; 6,090,751;6,096,329; 6,124,339; 6,180,798; 6,335,357; 6,350,771; 6,372,774;6,395,906; 6,413,542; 6,685,954; and 7,468,381. See also: EP 0 234 119,EP 0 295 117, EP 0 352 944, EP 0 500 209, EP 0 780 378, EP 0 846 686,and EP 0 948 485, all of which are incorporated herein by reference intheir entirety.

The compounds of the families defined in these patents are extremelyactive and one of these compounds,5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole,or fipronil, is particularly effective against pests, including fleasand ticks.

US 2008/031902 describes certain 1-arylpyrazole compounds that aresubstituted at the 5-position of the pyrazole ring with alkyl orC₁-C₄haloalkyl groups. These compounds were also found to beparticularly effective against fleas and ticks.

These compounds are given as having activity against a very large numberof parasites, including insects and acarines in fields as varied asagriculture, public health and veterinary medicine. The general teachingof these documents indicates that these active compounds may beadministered via different routes: oral, parenteral, percutaneous andtopical routes. Topical administration comprises, in particular, skinsolutions (pour-on or spot-on), sprays, drenches, baths, showers, jets,powders, greases, shampoos, creams, etc. The pour-on type skin solutionsmay be designed for percutaneous administration.

Notwithstanding the effectiveness of certain arylpyrazole compoundscertain parasites, it there continues to be a need for new formulationscomprising 1-arylpyrazoles in pharmaceutically acceptable carriers thatexhibit improved efficacy against parasites.

Other compounds that are known in the art to prevent, treat or controlendo- and ectoparasitic infestations include milbemycin or avermectinderivatives, which are natural or semi-synthetic compounds that containa 16-membered macrocyclic ring. The avermectin and milbemycin series ofcompounds are potent anthelmintic and antiparasitic agents against awide range of internal and external parasites. The natural productavermectins are disclosed in U.S. Pat. No. 4,310,519 toAlbers-Schonberg, et al., and the 22,23-dihydro-avermectin compounds aredisclosed in Chabala, et al., U.S. Pat. No. 4,199,569. For a generaldiscussion of avermectins, which include a discussion of their uses inhumans and animals, see “Ivermectin and Abamectin,” W. C. Campbell, ed.,Springer-Verlag, New York (1989). Naturally occurring milbemycins aredescribed in Aoki et al., U.S. Pat. No. 3,950,360.

Another family of parasiticides are the formamidines which include butare not limited to amitraz (MITABAN®, Pfizer; POINT-GUARD®, Intervet;PREVENTIC®, Virbac; TAKTIC®, Intervet), chlordimeform, chloromebuform,formetanate and formparanate. Amitraz is a well-knownacaracide/insecticide from the formamidine family acknowledged to beuseful as a miticidal agent and for the control of ticks. See Plumb'sVeterinary Drug Handbook (Fifth Edition), ed. Donald C. Plumb, BlackwellPublishing, pg. 34, (2005). The formamidine family of compounds isdistinguished by a characteristic —N═CR—NR′— moiety. Amitraz differsfrom other members of the formamidine family in that there are two suchmoieties in the compound. Amitraz has the following structure:

One problem associated with compositions comprising formamidinecompounds, including amitraz, is the lack of long-term stability undercertain conditions. For example, amitraz has been shown to degrade inaqueous solutions at certain pH ranges, as described, for example, in E.Corta, A. Bakkali, L. A. Berrueta, B. Gallo, F. Vicente, “Kinetics andMechanism of Amitraz Hydrolysis in Aqueous Media by HPLC and GC-MS”,Talanta 48 (1999) 189-199. Some amitraz degradates have further shownpesticidal efficacy, such as described, for example, in Osborne, M. P.,“Actions of Formamidines, Local Anesthetics, Octopamine and RelatedCompounds Upon the Electrical Activity of Neurohaemal Organs of theStick Insect (Carausius morosus) and Sense Organs of Fly Larvae (Muscademstica, Calliphora erythrocephala)”, Pesticide Biochemistry andPhysiology 23, 190-204 (1985).

Therefore, although formamidine parasiticides, including amitraz, haveconsiderable utility for treating and preventing parasitic infestations,there are several problems associated with using amitraz as aparasiticide in a commercial veterinary pharmaceutical product. Theseproblems include: (1) insufficient stability at certain pH values: whileamitraz is stable at higher pH values, amitraz tends to hydrolyze overtime at pH ranges commonly associated with physiological use (e.g. pH ofabout 5.0 to about 6.0); (2) amitraz is not effective for the control offleas; and (3) compositions comprising amitraz may not provide asufficiently long term shelf life in mixtures with some antiparisiticagents and certain carriers. For example, compositions containingamitraz may not have sufficient long term stability (shelf life) incertain solvent systems which are optimal for other antiparasitic agentswith which it may be combined.

Potential solutions to the stability problems have often resulted insolutions with long lasting odors or adverse reactions which renderedthese solutions unsuitable for once monthly pharmaceutical or veterinaryuse.

A composition comprising a 1-aryl-pyrazole with a formamidine compound,e.g. fipronil with amitraz, which exhibits synergistic efficacy againstectoparasites is described in U.S. Pat. No. 7,531,186 to Boeckh et al.;however certain embodiments of the composition, where a 1-arylpyrazoleand a formamidine are present together in certain carriers, may not havea sufficiently long storage shelf life. One possible reason for theinsufficient long term shelf life is that fipronil is stable at a pH ofabout 5.0 to about 6.0, while amitraz will degrade at this pH range.Thus, there remains a need in the art for formulations, methods ofstorage and methods of administration which provide 1-aryl-pyrazoles andformamidines in a synergistically active formulation to treat parasites.There also exists a need in the art to provide compositions comprisingamitraz which provide enhanced stability with other active agents,including 1-arylpyrazoles, and improved dissipation of odor.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

SUMMARY OF THE INVENTION

The present invention provides compositions and formulations comprisinga 1-arylpyrazole compound or a 1-arylpyrazole compound in combinationwith a formamidine compound, formulations and uses or veterinary usesthereof for the treatment or prophylaxis of parasitic infestations ofanimals (either wild or domesticated), including livestock and companionanimals such as cats, dogs, horses, chickens, sheep, goats, pigs,turkeys and cattle, with the aim of ridding these hosts of parasitescommonly encountered by such animals.

The invention also provides methods for the treatment or prevention ofparasitic infestations in animals, comprising administering an effectiveamount of a composition comprising at least one 1-arylpyrazole or a1-arylpyrazole in combination with at least one formamidine compound tothe animal. Surprisingly, it has been found that the inventivecompositions and formulations described herein exhibit superiorstability and synergistic efficacy against harmful parasites over a longduration compared to compositions known in the art. In particular, thepresent invention has surprisingly overcome the problems associated withthe instability of a formamidine in solution and the problems associatedwith the instability of a solution comprising a 1-arylpyrazole and aformamidine.

The compositions or formulations of the invention include spot-on,pour-on or spray formulations and may include a furtherectoparasiticide, such as an insect growth regulator (IGR), anavermectin or milbemycin derivative, an acaricide, a pyrethroidinsecticide, or an anthelmintic, such as benzimidazoles orimidazothiazoles.

One aspect of the invention provides compositions comprising at leastone 1-aryl-5-alkyl or 1-aryl-5-haloakylpyrazole compound of formula (IA)

wherein variables R_(2a), R_(3a), R_(4a), R_(6a) and R_(13a) are asdefined below, in combination with a veterinarily acceptable carrier,and optionally with at least one crystallization inhibitor.

Another object of the invention is to provide a composition for thetreatment and prevention of a parasitic infestation in an animalcomprising at least one 1-arylpyrazole compound in a first veterinarilyacceptable carrier, at least one formamidine compound in a secondveterinarily acceptable carrier, and optionally at least onecrystallization inhibitor; wherein the 1-arylpyrazole compound(s) andfirst veterinarily acceptable carrier are isolated and not in fluidcommunication with the formamidine compound(s) and the secondveterinarily acceptable carrier.

In some embodiments, the 1-arylpyrazole compounds have the formula (IB)shown below, where the variables R_(2b), R_(3b), R_(4b), R_(6b) and Zare described below.

In other embodiments, the formamidine compounds in the compositions ofthe invention have the formula (II) shown below, where variables R₁₄,R₁₅, R₁₆, R₁₇ and x are described below.

In some embodiments, the invention provides compositions and methodscomprising at least one 1-arylpyrazole compound in a first veterinarilyacceptable carrier and at least one formamidine compound in a secondveterinarily acceptable carrier, where the compounds and veterinarilyacceptable carriers are stored and administered from dual-cavitycontainers. The methods and compositions allow for stable synergisticcompositions comprising 1-arylpyrazole compounds and formamidinecompounds that have superior activity against parasites. In preferredembodiments, the 1-arylpyrazole compound is fipronil and the formamidinecompound is amitraz. In some embodiments, the 1-arylpyrazole compound(s)and the corresponding carrier is administered simultaneously with theformamidine compound(s) in a second carrier.

Also provided are stable formamidine compositions in certain carriers.In some embodiments, the carriers include solvents with dielectricconstants of about 2 to about 30 that are acceptable for pharmaceuticaland/or veterinary use. In other embodiments, the carriers includeaprotic solvents or polar aprotic solvents. In still other embodiments,the carrier includes aprotic solvents or polar aprotic solvents withdielectric constants of about 2 to about 30. In some embodiments, theformamidine compositions comprising a mixture of at least two solventswith dielectric constants of about 2 to about 30 exhibit surprisinglyimproved odor dissipation compared to prior art compositions.

The invention also provides a kit for the treatment or prevention of aparasitic infestation in an animal, which comprises at least one1-arylpyrazole compound in a first veterinarily acceptable carrier, atleast one formamidine compound in a second veterinarily acceptablecarrier, and a multiple cavity container; wherein the one or more1-arylpyrazole compound(s) in the first veterinarily acceptable carrieris in a first cavity of the multiple cavity container and the one ormore formamidine compound(s) and the second veterinarily acceptablecarrier are in a second cavity of the multiple cavity container.

Accordingly, it is an object of the invention to not encompass withinthe invention any previously known product, process of making theproduct, or method of using the product such that the Applicants reservethe right and hereby disclose a disclaimer of any previously knownproduct, process, or method. It is further noted that the invention doesnot intend to encompass within the scope of the invention any product,process, or making of the product or method of using the product, whichdoes not meet the written description and enablement requirements of theUSPTO (35 U.S.C. §112, first paragraph) or the EPO (Article 83 of theEPC), such that Applicants reserve the right and hereby disclose adisclaimer of any previously described product, process of making theproduct, or method of using the product.

These and other embodiments are disclosed or are obvious from andencompassed by, the following Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of an embodiment of a container.

FIG. 2 is a side view of an embodiment of a container.

FIG. 3 is a side view of an embodiment of a container.

FIG. 4 is a side view of an embodiment of a container.

FIG. 5 is a top view of an embodiment of a container.

FIG. 6 is a top view of an embodiment of a container.

FIG. 7 is a top view of an embodiment of a strip of 3 containers.

FIG. 8 is a 3CAD view top view of an embodiment of an individual smallcontainer.

FIGS. 9 a and 9 b are 3CAD views of an embodiment of an individual largecontainer.

FIG. 10 shows the effect of fipronil alone, amitraz alone and afipronil/amitraz combination on the geometric mean of tick motility overtime

FIG. 11 shows the % efficacy of various compositions of the inventionagainst fleas in dogs.

FIG. 12 shows the % efficacy of various compositions of the inventionagainst fleas in cats.

DETAILED DESCRIPTION

The present invention provides novel and inventive compositions andformulations comprising at least one 1-arylpyrazole compound alone or incombination nation with one or more formamidine compound(s) and aveterinarily acceptable carrier or diluent. Also provided are methodsand uses for the treatment or prophylaxis of parasitic infections andinfestations of animals, comprising administering an effective amount ofa composition of the invention to the animal. Surprisingly, it has beenfound that the inventive compositions and formulations described hereincomprising a 1-arylpyrazole compound alone or in combination with aformamidine compound exhibit superior stability and efficacy, includingsynergistic efficacy in some embodiments, against harmful parasites. Inparticular, the present invention has surprisingly overcome the problemsassociated with the lack of long term stability of a formamidine insolution and the problems associated with the insufficient shelf life ofa composition comprising a 1-arylpyrazole and a formamidine in certaincarriers.

The invention includes at least the following features:

(a) In one embodiment, the invention provides novel compositionscomprising at least one 1-arylpyrazole of formula (I), or veterinarilyacceptable salts thereof, together with a veterinarily acceptablecarrier or diluent, that exhibit superior activity against animalparasites and improved stability;

(b) veterinary compositions comprising at least one formamidine offormula (II), or veterinarily acceptable salts thereof, together with aveterinarily acceptable carrier or diluent, that exhibit improvedstability;

(c) veterinary composition comprising at least one 1-arylpyrazole offormula (I) and a formamidine of formula (II), or veterinarilyacceptable salts thereof, together with one or more veterinarilyacceptable carrier(s) or diluent(s), that exhibits synergistic efficacyagainst animal parasites and improved stability;

(d) methods for the treatment or prevention of parasitic infestations inan animal comprising administering an effective amount of a compositioncomprising at least one 1-arylpyrazole of formula (I), or veterinarilyacceptable salts thereof, to the animal in a veterinarily acceptablecarrier or diluent;

(e) methods for the treatment or prevention of parasitic infestations inanimals comprising administering an effective amount of a compositioncomprising at least one formamidine of formula (II), or veterinarilyacceptable salts thereof, in a veterinarily acceptable carrier ordiluent, wherein the formamidine exhibits superior stability insolution;

(f) methods for the treatment or prevention of parasitic infestations inanimals comprising administering an effective amount of at least one1-arylpyrazole of formula (I) and at least one formamidine of formula(II), or veterinarily acceptable salts thereof, together withveterinarily acceptable carriers or diluents, wherein the1-arylpyrazole(s) and the formamidine compound(s) are administered inseparate carriers;

(g) methods for the treatment or prevention of parasitic infestations inanimals comprising administering an effective amount of at least one1-arylpyrazole of formula (I) and at least one formamidine of formula(II), or veterinarily acceptable salts thereof, together withveterinarily acceptable carriers or diluents, wherein the1-arylpyrazole(s) and the formamidine compound(s) are administeredsimultaneously;

(h) methods for the treatment or prevention of parasitic infestations inanimals comprising administering an effective amount of at least one1-arylpyrazole of formula (I) and at least one formamidine of formula(II), or veterinarily acceptable salts thereof, together withveterinarily acceptable carriers or diluents, wherein the1-arylpyrazole(s) and the formamidine(s) are administered simultaneouslyand the 1-arylpyrazole(s) and the formamidine(s) are in separatecarriers;

(i) methods for the treatment or prevention of parasitic infestations inanimals comprising administering an effective amount of at least one1-arylpyrazole of formula (I) and at least one formamidine of formula(II), or veterinarily acceptable salts thereof, together withveterinarily acceptable carriers or diluents, wherein 1-arylpyrazole(s)and the formamidine(s) are administered simultaneously using adual-cavity container that holds the 1-arylpyrazole and the formamidinein separate carriers; and

(j) a dual-cavity container for storing and administering thecompositions of the invention, wherein the container comprises a firstcavity defined by a front wall and a divider wall, and a second cavitydefined by a rear wall and a divider wall.

In this disclosure and in the claims, terms such as “comprises,”“comprising,” “containing” and “having” and the like can have themeaning ascribed to them in U.S. patent law and can mean “includes,”“including,” and the like; “consisting essentially of” or “consistsessentially” likewise has the meaning ascribed in U.S. patent law andthe term is open-ended, allowing for the presence of more than thatwhich is recited so long as basic or novel characteristics of that whichis recited is not changed by the presence of more than that which isrecited, but excludes prior art embodiments.

It is also noted that in this disclosure and in the claims and/orparagraphs, the compounds of the invention are intended to include allstereoisomers and crystalline forms (which includes hydrated forms,polymorphic forms and amorphous forms with up to 15% by weightcrystalline structure) thereof.

DEFINITIONS

Terms used herein will have their customary meaning in the art unlessspecified otherwise. The organic moieties mentioned in the definitionsof the variables of formula (I) or (II) are—like the termhalogen—collective terms for individual listings of the individual groupmembers. The prefix C_(n)-C_(m) indicates in each case the possiblenumber of carbon atoms in the group.

The term “animal” is used herein to include all mammals, birds and fishand also include all vertebrate animals, including humans. Animalsinclude, but are not limited to, humans, cats, dogs, cattle, chickens,cows, deer, goats, horses, llamas, pigs, sheep and yaks. It alsoincludes an individual animal in all stages of development, includingembryonic and fetal stages.

The term “alkyl” refers to saturated straight, branched, cyclic,primary, secondary or tertiary hydrocarbons, including those having 1 to20 atoms. In some embodiments, alkyl groups will include C₁-C₁₂, C₁-C₁₀,C₁-C₈, C₁-C₆ or C₁-C₄ alkyl groups. Examples of C₁-C₁₀ alkyl include,but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,2-ethylhexyl, nonyl and decyl and their isomers. C₁-C₄-alkyl means forexample methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups, which are encompassed by alkyl, may be referred toas “cycloalkyl” and include those with 3 to 10 carbon atoms havingsingle or multiple condensed rings. In some embodiments, cycloalkylgroups include C₄-C₇ or C₃-C₄ cyclic alkyl groups. Non-limiting examplesof cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The alkyl and cycloalkyl groups described herein can be unsubstituted orsubstituted with one or more moieties selected from the group consistingof alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino,alkyl- or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano,azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl,sulfinyl, sulfamonyl, ester, phosphonyl, phosphinyl, phosphoryl,phosphine, thioester, thioether, acid halide, anhydride, oxime,hydrozine, carbamate, phosphonic acid, phosphate, phosphonate, or anyother viable functional group that does not inhibit the biologicalactivity of the compounds of the invention, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Third Edition, 1999, hereby incorporatedby reference.

The term “alkenyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon double bond. In some embodiments,alkenyl groups may include C₂-C₂₀ alkenyl groups. In other embodiments,alkenyl includes C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkenyl groups.In one embodiment of alkenyl, the number of double bonds is 1-3, inanother embodiment of alkenyl, the number of double bonds is one or two.Other ranges of carbon-carbon double bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. “C₂-C₁₀-alkenyl” groups may include more than one double bondin the chain. Examples include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

“Cycloalkenyl” refers to monovalent cyclic alkenyl groups of from 4 to10 carbon atoms, preferably 5 to 8 carbon atoms, having single ormultiple condensed rings which condensed rings may or may not becycloalkenyl provided that the point of attachment is to a cycloalkenylring atom. Examples of cycloalkenyl groups include, by way of example,cyclopenten-4-yl, cyclooctene-5-yl and the like. Alkenyl andcycloalkenyl groups may be unsubstituted or substituted with one or moresubstituents as described for alkyl above.

“Alkynyl” refers to both straight and branched carbon chains which haveat least one carbon-carbon triple bond. In one embodiment of alkynyl,the number of triple bonds is 1-3; in another embodiment of alkynyl, thenumber of triple bonds is one or two. In some embodiments, alkynylgroups include from C₂-C₂₀ alkynyl groups. In other embodiments, alkynylgroups may include C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkynyl groups.Other ranges of carbon-carbon triple bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. For example, the term “C₂-C₁₀-alkynyl” as used herein refersto a straight-chain or branched unsaturated hydrocarbon group having 2to 10 carbon atoms and containing at least one triple bond, such asethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl,n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl,n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl,n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl,3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl,n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl,n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl,n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl,3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl,4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term “haloalkyl” refers to an alkyl group, as defined herein, whichis substituted by one or more halogen atoms. For example C₁-C₄-haloalkylincludes, but is not limited to, chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl andthe like.

The term “fluoroalkyl” as used herein refers to an alkyl in which one ormore of the hydrogen atoms is replaced with fluorine atoms, for exampledifluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl orpentafluoroethyl.

The term “haloalkenyl” refers to an alkenyl group, as defined herein,which is substituted by one or more halogen atoms.

The term “haloalkynyl” refers to an alkynyl group, as defined herein,which is substituted by one or more halogen atoms.

“Alkoxy” refers to alkyl-O—, wherein alkyl is as defined above.Similarly, the terms “alkenyloxy,” “alkynyloxy,” “haloalkoxy,”“haloalkenyloxy,” “haloalkynyloxy,” “cycloalkoxy,” “cycloalkenyloxy,”“halocycloalkoxy,” and “halocycloalkenyloxy” refer to the groupsalkenyl-O—, alkynyl-O—, haloalkyl-O—, haloalkenyl-O—, haloalkynyl-O—,cycloalkyl-O—, cycloalkenyl-O—, halocycloalkyl-O—, andhalocycloalkenyl-O—, respectively, wherein alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, andhalocycloalkenyl are as defined above. Examples of C₁-C₆-alkoxy include,but are not limited to, methoxy, ethoxy, C₂H₅—CH₂O—, (CH₃)₂CHO—,n-butoxy, C₂H₅—CH(CH₃)O—, (CH₃)₂CH—CH₂O—, (CH₃)₃CO—, n-pentoxy,1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy,1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxyand the like.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring or multiple condensed rings. In someembodiments, aryl groups include C₆-C₁₀ aryl groups. Aryl groupsinclude, but are not limited to, phenyl, biphenyl, naphthyl,tetrahydronaphtyl, phenylcyclopropyl and indanyl. Aryl groups may beunsubstituted or substituted by one or more moieties selected fromhalogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl,halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy,haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy,cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio,haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl,alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl,haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl,haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino,alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, ortrialkylsilyl.

The term “aralkyl” refers to an aryl group that is bonded to the parentcompound through a diradical alkylene bridge, (—CH₂—)_(n), where n is1-12 and where “aryl” is as defined above.

“Heteroaryl” refers to a monovalent aromatic group of from 1 to 15carbon atoms, preferably from 1 to 10 carbon atoms, having one or moreoxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfurheteroatoms may optionally be oxidized. Such heteroaryl groups can havea single ring (e.g., pyridyl or furyl) or multiple condensed ringsprovided that the point of attachment is through a heteroaryl ring atom.Preferred heteroaryls include pyridyl, piridazinyl, pyrimidinyl,pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl benzofuranyl,and benzothiophenyl. Heteroaryl rings may be unsubstituted orsubstituted by one or more moieties as described for aryl above.

“Heterocyclyl,” “heterocyclic” or “heterocyclo” refer to fully saturatedor unsaturated, cyclic groups, for example, 3 to 7 membered monocyclicor 4 to 7 membered monocyclic; 7 to 11 membered bicyclic, or 10 to 15membered tricyclic ring systems, which have one or more oxygen, sulfuror nitrogen heteroatoms in ring, preferably 1 to 4 or 1 to 3heteroatoms. The nitrogen and sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom ofthe ring or ring system and may be unsubstituted or substituted by oneor more moieties as described for aryl groups above.

Exemplary monocyclic heterocyclic groups include, but are not limitedto, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl,4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include, but are not limited to,indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

Alkoxycarbonyl refers to —C(═O)—O-alkyl, wherein alkoxy is as definedabove;

Halogen means the atoms fluorine, chlorine, bromine and iodine. Thedesignation of “halo” (e.g. as illustrated in the term haloalkyl) refersto all degrees of substitutions from a single substitution to a perhalosubstitution (e.g. as illustrated with methyl as chloromethyl (—CH₂Cl),dichloromethyl (—CHCl₂), trichloromethyl (—CCl₃)).

Stereoisomers and Polymorphic Forms

It will be appreciated by those of skill in the art that the compoundswithin the compositions of the invention may exist and be isolated asoptically active and racemic forms. Compounds having one or more chiralcenters, including at a sulfur atom, may be present as singleenantiomers or diastereomers or as mixtures of enantiomers and/ordiastereomers. For example, it is well known in the art that sulfoxidecompounds may be optically active and may exist as single enantiomers orracemic mixtures. In addition, compounds within the compositions of theinvention may include one or more chiral centers, which results in atheoretical number of optically active isomers. Where compounds withinthe compositions of the invention include n chiral centers, thecompounds may comprise up to 2^(n) optical isomers. The presentinvention encompasses the specific enantiomers or diastereomers of eachcompound as well as mixtures of different enantiomers and/ordiastereomers of the compounds of the invention that possess the usefulproperties described herein. The optically active forms can be preparedby, for example, resolution of the racemic forms by selectivecrystallization techniques, by synthesis from optically activeprecursors, by chiral synthesis, by chromatographic separation using achiral stationary phase or by enzymatic resolution.

The compounds within the compositions of present invention may also bepresent in different solid forms such as different crystalline forms orin the form of an amorphous solid. The present invention encompassesdifferent crystalline forms as well as amorphous forms of the inventivecompounds.

In addition, the compounds within the compositions of the invention mayexist as hydrates or solvates, in which a certain stoichiometric amountof water or a solvent is associated with the molecule in the crystallineform. The hydrates and solvates of the compounds of formula (I) or (II)are also the subject of the invention.

Salts

Also contemplated within the scope of the invention are acid or basesalts, where applicable, of the compounds of the invention provided forherein.

The term “acid” contemplates all pharmaceutically acceptable inorganicor organic acids. Inorganic acids include mineral acids such ashydrohalic acids such as hydrobromic acid and hydrochloric acid,sulfuric acid, phosphoric acids and nitric acid. Organic acids includeall pharmaceutically acceptable aliphatic, alicyclic and aromaticcarboxylic acids, dicarboxylic acids, tricarboxylic acids and fattyacids. In one embodiment of the acids, the acids are straight chain orbranched, saturated or unsaturated C₁-C₂₀ aliphatic carboxylic acids,which are optionally substituted by halogen or by hydroxyl groups, orC₆-C₁₂ aromatic carboxylic acids. Examples of such acids are carbonicacid, formic acid, acetic acid, propionic acid, isopropionic acid,valeric acid, α-hydroxy acids such as glycolic acid and lactic acid,chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylicacid. Examples of dicarboxylic acids include oxalic acid, malic acid,succinic acid, tartaric acid, fumaric acid, and maleic acid. An exampleof a tricarboxylic acid is citric acid. Fatty acids include allpharmaceutically or veterinarily acceptable saturated or unsaturatedaliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms.Examples include butyric acid, isobutyric acid, sec-butyric acid, lauricacid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenicacid, and phenylsteric acid. Other acids include gluconic acid,glycoheptonic acid and lactobionic acid.

The term “base” contemplates all pharmaceutically or veterinarilyacceptable inorganic or organic bases, including hydroxides, carbonatesor bicarbonates of alkali metal or alkaline earth metals. Salts formedwith such bases include, for example, the alkali metal and alkalineearth metal salts, including, but not limited to, as the lithium,sodium, potassium, magnesium or calcium salts. Salts formed with organicbases include the common hydrocarbon and heterocyclic amine salts, whichinclude, for example, ammonium salts (NH4⁺), alkyl- and dialkylammoniumsalts, and salts of cyclic amines such as the morpholine and piperidinesalts.

A first aspect of the invention provides a formulation with increasedstability and/or efficacy for treating or preventing an infestation ofan animal with ectoparasites and/or endoparasites comprising:

(a) a 1-aryl pyrazole compound of formula (I), or a veterinarilyacceptable salt thereof:

wherein:

R₁ is hydrogen, cyano, nitro, halogen, R₃, R₈, formyl, —C(O)R₈,—C(O)OR₈, —C(O)NR₉R₁₀, —C(═NOH)NH₂, —C(═NNH₂), or —C(S)NH₂;

R₂ is R₈, halogen, cyano, nitro, —SCN, 4-5-dicyanoimidazol-2-yl, or—S(O)_(m)R₁₁;

R₃ is alkyl, haloalkyl, OH, or NR₉R₁₀;

R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl, haloalkyl,cyano or nitro;

R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro,—C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;

Z is a nitrogen atom or C—R₁₃;

R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R₉ is hydrogen, alkyl, haloalkyl or alkoxy;

R₁₀ is hydrogen, alkyl, haloalkyl, alkoxy, or —C(O)R₈;

wherein said alkyl, haloalkyl, alkoxy, or —C(O)R₈ groups are optionallysubstituted with alkyl, haloalkyl, cycloalkyl, alkoxy, aryl, orheteroaryl; wherein said aryl or heteroaryl groups are optionallysubstituted with one or more groups selected from the group consistingof alkyl, cycloalkyl, haloalkyl, aryl, halogen, C(O)R₈, —C(O)OR₈,—C(O)NR₉R₉, —C(S)NH₂, or —S(O)_(m)R₁₁

R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl orcycloalkyl;

R₁₂ is alkyl or haloalkyl;

R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy orhaloalkoxy;

m is 0, 1 or 2; and

n is 0, 1 or 2; or

a salt thereof;

(b) a pharmaceutical or veterinarily acceptable carrier vehicle; and

(c) optionally, a crystallization inhibitor.

Compounds of formula (I) and methods for preparing the compounds aredescribed, for example, in U.S. Pat. Nos. 6,096,329; 6,395,765;6,685,954; 6,867,229; EP 0 205 117 and WO 87/03781, all of which areincorporated herein by reference in their entirety.

It is a second aspect of the invention to provide for formulationscomprising 1-arylpyrazole compounds that exhibit improved efficacyand/or stability. It has been surprisingly been discovered that spot-on,pour-on or spray-on formulations of 1-arylpyrazole compounds in certaincarriers exhibit enhanced stability and/or efficacy againstectoparasites and/or endoparasites compared to formulations of1-arylpyrazoles of the prior art.

In one embodiment, the pharmaceutically or veterinarily acceptablecarrier comprises acetone, acetonitrile, benzyl alcohol, ethanol,isopropanol, diisobutyl adipate, diisopropyl adipate (also known asCERAPHYL 230), butyl diglycol, dipropylene glycol n-butyl ether,ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols,propylene glycol monomethyl ether, propylene glycol monoethyl ether,2-pyrrolidone including N-methylpyrrolidone, diethylene glycol monoethylether, triacetin, butyl acetate, octyl acetate, propylene carbonate,butylene carbonate, dimethyl sulfoxide, amides includingdimethylformamide and dimethylacetamide, or any combination thereof.

In one preferred embodiment of the invention, the pharmaceutically orveterinarily acceptable carrier of the formulation includes C₁-C₁₀alcohols or esters thereof (including acetates, such as ethyl acetate,butyl acetate and the like), C₁₀-C₁₈ saturated fatty acids or estersthereof, C₁₀-C₁₈ monounsaturated fatty acids or esters thereof,monoesters or diesters of aliphatic diacids, glycerol monoesters (e.g.monoglycerides), glycerol diesters (e.g. diglycerides), glyceroltriesters (e.g. triglycerides such as triacetin), glycols, glycolethers, glycol esters or glycol carbonates, polyethylene glycols ofvarious grades (PEGs) or monoethers, diethers, monoesters or diestersthereof (e.g. diethylene glycol monoethyl ether), or mixtures thereof.

In another embodiment of the invention, the carrier may includediisopropyl adipate, dipropylene glycol monomethyl ether, propyleneglycol monomethyl ether, 2-pyrrolidone including N-methylpyrrolidone,diethylene glycol monoethyl ether, triacetin, butyl acetate, octylacetate, propylene carbonate, oleic acid, or a mixture of at least twoof these solvents.

In yet another embodiment of the invention, the carrier may includetriacetin or diethylene glycol monoethyl ether.

It is a further aspect of the invention to provide for formulations withenhanced efficacy against ectoparasites, such as fleas, ticks, mites,mosquitoes, flies and lice. The invention may also be effective againstendoparasites, cestodes, nematodes, such as filariae, and roundworms ofthe digestive tract of animals and humans.

In another embodiment of the invention, the pharmaceutically orveterinarily acceptable carrier is an organic solvent commonly used inthe formulation art. These organic solvents may be found, for example,in Remington Pharmaceutical Sciences, 16^(th) Edition (1986). Thesesolvents include, for example, acetone, ethyl acetate, methanol,ethanol, isopropanol, dimethylformamide, dichloromethane or diethyleneglycol monoethyl ether (TRANSCUTOL), diisobutyl adipate, diisopropyladipate (CERAPHYL 230), butyl diglycol, dipropylene glycol n-butylether, ethylene glycol monoethyl ether, ethylene glycol monomethylether, dipropylene glycol monomethyl ether, liquid polyoxyethyleneglycols, propylene glycol monomethyl ether, propylene glycol monoethylether, 2-pyrrolidone including N-methylpyrrolidone, diethylene glycolmonoethyl ether, triacetin, acetates of C₁-C₁₀ alcohols, C₁₀-C₁₈monounsaturated fatty acids or esters thereof, propylene carbonate,butylene carbonate, or any combination thereof. These solvents can besupplemented by various excipients according to the nature of thedesired phases, such as C₈-C₁₀ caprylic/capric triglyceride (ESTASAN orMIGLYOL 812), oleic acid or propylene glycol.

In one embodiment, the invention provides a formulation that comprises a1-arylpyrazole of formula (I) wherein R₁ is cyano, —C(O)R₈, —C(O)OR₈,—C(O)NR₉R₁₀, —C(═NOH)NH₂, —C(═NNH₂), or —C(S)NH₂, and all the othervariables are as defined above.

In another embodiment, the invention provides a formulation comprising a1-arylpyrazole of formula (I) wherein R₃ is alkyl or haloalkyl.

In one embodiment, the invention provides a formulation comprising a1-arylpyrazole of formula (I) wherein:

R₁ is cyano, —C(O)R₈, —C(O)OR₈, —C(O)NR₉R₁₀, —C(═NOH)NH₂, —C(═NNH₂), or—C(S)NH₂; and

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R₁₁.

In another embodiment, the invention provides a formulation comprising a1-arylpyrazole of formula (I) wherein:

R₁ is cyano, —C(O)R₈, —C(O)OR₈, —C(O)NR₉R₁₀, —C(═NOH)NH₂, —C(═NNH₂), or—C(S)NH₂;

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R₁₁; and

R₃ is alkyl or haloalkyl.

In still another embodiment, the invention provides a formulationcomprising a 1-arylpyrazole of formula (I) wherein:

R₁ is cyano;

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R₁₁;

R₃ is alkyl or haloalkyl;

R₄, R₅ and R₇ are independently hydrogen, or halogen; and

Z is C—R₁₃.

In another embodiment, the invention provides a formulation comprising a1-arylpyrazole of formula (I) wherein:

R₁ is cyano;

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R₁₁;

R₃ is C₁-C₄alkyl or C₁-C₄haloalkyl;

R₆ is halogen, haloalkyl or SF₅; and

Z is C—R₁₃.

In one embodiment, the invention provides a formulation comprising a1-arylpyrazole of formula (I) wherein:

R₁ is cyano;

R₂ is —S(O)_(m)R₁₁;

R₃ is C₁-C₄alkyl, C₁-C₄haloalkyl, or NR₉R₁₀;

R₄, R₅ and R₇ are independently hydrogen, or halogen;

R₆ is halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, or SF₅;

Z is C—R₁₃; and

R₁₃ is halogen or C₁-C₄haloalkyl.

In another embodiment of the formulation, a 1-arylpyrazole of formula(I) is provided wherein:

R₁ is cyano;

R₂ is —S(O)_(m)R₁₁;

R₃ is methyl, ethyl, propyl, or C₁-C₄haloalkyl;

R₄ is halogen;

R₅ and R₇ are hydrogen;

R₆ is C₁-C₄haloalkyl;

Z is C—R₁₃;

R₁₁ is —CF₃, —CClF₂, or CFCl₂; and

R₁₃ is halogen.

In still another embodiment, the invention provides a formulationcomprising a 1-arylpyrazole of formula (I) wherein:

R₁ is cyano;

R₂ is —S(O)_(m)R₁₁;

R₃ is methyl or ethyl;

R₄ is chloro or fluoro;

R₅ and R₇ are hydrogen;

R₆ is —CF₃;

Z is C—R₁₃;

R₁₁ is —CFCl₂; and

R₁₃ is chloro or fluoro.

In another embodiment, the invention provides a formulation comprising a1-aryl-alkyl or 5-haloalkylpyrazole of formula (I) that has thestructure of formula (IA) below in combination with a veterinarilyacceptable carrier and optionally a crystallization inhibitor:

or a salt thereof, wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl, ethyl or C₁-C₄ haloalkyl;

R_(4a) is halogen;

R_(6a) is C₁-C₄ alkyl or haloalkyl;

R_(13a) is halogen;

R_(11a) is C₁-C₄ haloalkyl; and

m is 0, 1 or 2.

Compounds of formula (IA) as well as process for the preparation ofthese compounds are described in US 2008/0031902 A1 to Lee et al., whichis incorporated herein by reference in its entirety.

In another embodiment, the invention provides a formulation thatcomprises a 1-aryl-5-alkyl pyrazole compound of formula (IA) wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl, or ethyl;

R_(4a) is halogen;

R_(6a) is C₁-C₄ haloalkyl;

R_(13a) is halogen;

R_(11a) is —CF₃, —CClF₂, or —CFCl₂; and

m is 0, 1 or 2.

In another embodiment, the invention provides a formulation thatcomprises a 1-aryl-5-alkyl pyrazole compound of formula (IA) wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl, or ethyl;

R_(4a) is halogen;

R_(6a) is C₁-C₄ haloalkyl;

R_(13a) is halogen;

R_(11a) is —CF₃, —CClF₂, or —CFCl₂; and

m is 0, 1 or 2.

In still another embodiment of the invention, a formulation is providedthat comprises a 1-aryl-5-alkyl pyrazole compound of formula (IA)wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl;

R_(4a) is —Cl;

R_(6a) is —CF₃;

R_(13a) is —F;

R_(11a) is —CFCl₂; and

m is 0, 1 or 2.

In another embodiment, the invention provides a formulation comprising3-cyano-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-dichlorofluoromethylsulfinyl-5-methyl-1H-pyrazole(Compound 1) in combination with a pharmaceutically or veterinarilyacceptable carrier and optionally a crystallization inhibitor.

It has been surprisingly discovered that 1-aryl-5-alkyl or 5-haloalkylpyrazole compounds are highly efficacious against ectoparasites andprovide long-lasting protection against ectoparasites for at least 30,at least 40 or at least 60 days. Thus, 1-aryl-5-alkyl or 5-haloalkylpyrazoles of formula (IA) are extremely useful and offer substantialadvantages to other paraciticidal compounds. Furthermore, it has beendiscovered that 1-aryl-5-alkyl or 5-haloalkyl pyrazole compounds offormula (IA) are able to eradicate parasites, particularly fleas andticks, from animals more quickly than other parasiticides.

A third aspect of the invention provides a composition comprising one ormore formamidine compounds including, but not limited to amitraz, thatexhibits enhanced stability. The formamidine compositions of theinvention typically comprise amitraz in combination with an aproticsolvent. In preferred embodiments, the compositions comprise aveterinarily effective amount of a formamidine in combination with apolar aprotic solvent. Aprotic solvents and polar aprotic solvents arewell known in the art, and the invention provides compositionscomprising any veterinarily acceptable aprotic or polar aprotic solventthat provides sufficient solubility for the formamidine compound may beused. Particularly preferred polar aprotic solvents include carboxylicacid esters, ketones and aryl ethers.

In other embodiments, the stable formamidine compositions of theinvention comprise a veterinarily effective amount of one or moreformamidine compounds and solvent with a dielectric constant of about 2to about 30. In some preferred embodiments, the stable formamidinecompositions of the invention comprise aprotic solvents that have adielectric constant of about 2 to about 30. In still more preferredembodiments, the stable formamidine compositions comprise polar aproticsolvents that have a dielectric constant of about 2 to about 30.

In other embodiments of the invention, the carrier comprises a solventwith a dielectric constant of about 2 to about 40, 2 to about 20, 5 toabout 30, or 10 to about 30. Preferably, the solvent with dielectricconstants of about 2 to about 40 is an aprotic solvent or a polaraprotic solvent.

In other embodiments, the carrier comprises one or more solvents with adielectric constant of about 2 to about 15 or about 3 to about 10. Instill another embodiment, the dielectric constant of the one or moresolvents is about 3.5 to about 10. In another embodiment, the dielectricconstant of the one or more solvents is about 4 to about 6.5.

In other embodiments of the invention, the carrier comprises one or moreaprotic solvents with dielectric constants of about 2 to about 40, 2 toabout 20, 5 to about 30, or 10 to about 30.

In other embodiments, the carrier comprises one or more aprotic solventswith dielectric constants of about 2 to about 15 or about 3 to about 10.In still another embodiment, the dielectric constant of the one or moreaprotic solvents is about 3.5 to about 10. In another embodiment, thedielectric constant of the one or more aprotic solvents is about 4 toabout 6.5.

In other embodiments of the invention, the carrier comprises one or morepolar aprotic solvents with dielectric constants of about 2 to about 40,2 to about 20, 5 to about 30, or 10 to about 30.

In other embodiments, the carrier comprises one or more polar aproticsolvents with dielectric constants of about 2 to about 15 or about 3 toabout 10. In still another embodiment, the dielectric constant of theone or more polar aprotic solvents is about 3.5 to about 10. In anotherembodiment, the dielectric constant of the one or more polar aproticsolvents is about 4 to about 6.5.

In one embodiment, the carrier comprises a single solvent with adielectric constant of about 2 to about 30. In still another embodiment,the carrier comprises a mixture of two or more solvents with adielectric constant of about 2 to about 30, which may preferably beaprotic or polar aprotic.

In still another embodiment, the carrier comprises a solvent with adielectric constant of about 2 to about 30 in combination with one ormore solvents that do not have a dielectric constant of about 2 to about30.

In other embodiments, the solvent in the stable formamidine compositionswill contain less than about 0.5% or less than about 0.3% (w/w) water.In other embodiments, the solvent will typically contain less than 0.2%(w/w) water. Preferably, the solvent will contain less than about 0.1%,or less than about 0.05% or less than about 0.025% (w/w) water. In otherembodiments, the solvent will contain from about 0.0001% (w/w) to about0.5% (w/w) water. More typically, the solvent will contain about 0.0001%to about 0.3%, about 0.001% to about 0.3%, about 0.001% to about 0.1% orabout 0.001% to about 0.05% (w/w) water. Preferably, the solvent willcontain from about 0.001% to about 0.025% (w/w) water. As discussedabove, amitraz has been shown to be unstable in aqueous solutions atcertain pH ranges or solutions containing significant amounts of waterat certain pH ranges.

Furthermore, it has been found that formamidine compounds, and amitrazin particular, may not have sufficient long term stability in certainsolvent systems. For example, in certain solvent systems amitraz may notprovide a sufficient shelf life for use as a commercial veterinarypharmaceutical product. Therefore, compositions of formamidines incertain carriers that exhibit enhanced stability are highly desired.

In one embodiment, the invention provides a composition comprising aformamidine, including amitraz, in combination with a suitable carrierthat is stable for up to about 2 months at about 50° C. It will beappreciated by those of skill in the art that a stable compositioncomprising a formamidine, as described herein, will show less than about5% degradation of the formamidine compound at the indicated conditions(temperature and relative humidity) relative to the initial measure ofpurity or concentration, as tested by a suitable stability-indicatingmethod for a given period of time. Preferably, the stability of aformulation is evaluated by HPLC by measuring the change inconcentration of the active in the formulation over time against areference standard.

In another embodiment, the invention provides a composition comprising aformamidine, including amitraz, that is stable for at least about 3months at about 50° C. In still other embodiments, the inventionprovides a composition comprising a formamidine, including amitraz, thatis stable for at least about 4 months, at least about 5 months or atleast about 6 months at about 50° C.

In another embodiment, the invention provides a composition comprising aformamidine compound, including amitraz, that is stable for at least 3months at about 40° C. and about 75% relative humidity (RH). In stillanother embodiment, the composition comprising a formamidine compoundwill be stable for at least 6 months at about 40° C. and 75% RH. Instill another embodiment, the composition comprising a formamidine willbe stable for at least 9 months at about 40° C. and 75% RH.

In another embodiment, the invention provides a composition comprising aformamidine, including amitraz, that is stable for at least about 12months at about 25° C. and about 60% RH. In other embodiments, theinvention provides a composition comprising a formamidine, includingamitraz, that is stable for at least about 18 months, about 24 months orabout 36 months at about 25° C. and about 60% RH.

In some embodiments, the invention provides stable compositionscomprising a formamidine in combination with one or more of amidesincluding dimethylformamide, dimethylacetamide, N-methylpyrrolidone andthe like; one or more sulfoxides including dimethyl sulfoxide and thelike; and combinations thereof.

In one embodiment, the solvent includes aryl ethers includingalkoxybenzene compounds; carboxylic acid esters, including aliphatic andaromatic carboxylic acids such as benzoic acid esters, and compoundswith multiple carboxylate groups; aliphatic ketones, saturated aliphaticketones, cyclic ketones, or mixtures thereof.

In another embodiment, the solvent includes C₁-C₁₀ carboxylic acidesters, phenyl carboxylic acid esters, carboxylic acid benzyl esters,benzoic acid C₁-C₄ alkyl esters, C₁-C₆ saturated aliphatic ketones, andmixtures thereof.

Examples of carboxylic acid esters include, but are not limited toC₁-C₂₀ alkyl esters of alkanoic acids. In one embodiment, the solventincludes C₁-C₂₀ alkyl esters of C₁-C₁₂ alkanoic acids. In otherembodiments, the solvent includes C₁-C₁₂ alkyl esters of C₁-C₁₂ alkanoicacids, C₁-C₁₂ alkyl esters of C₁-C₁₀ alkanoic acids, C₁-C₁₂ alkyl estersof C₁-C₈ alkanoic acids, C₁-C₁₂ alkyl esters of C₁-C₆ alkanoic acids orC₁-C₁₂ alkyl esters of C₁-C₄alkanoic acids. In various embodiments, thesolvent includes C₁-C₁₂ alkyl esters of formic acid, acetic acid,propionic acid, butanoic acid, pentanoic acid, isobutanoic acid,hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoicacid, and the like.

Also encompassed by the invention are phenyl and benzyl esters of alkylcarboxylic acids. Other carboxylic acid esters include C₁-C₂₀ alkylesters of di-carboxylic and tri-carboxylic acids including, but notlimited to, malonic acid, succinic acid, glutaric acid, adipic acid,citric acid, and the like.

Aromatic carboxylic acid esters are also contemplated, including C₁-C₂₀alkyl esters of aromatic carboxylic acids as well as well as benzylesters of aromatic carboxylic acids. Non-limiting examples of aromaticcarboxylic acids include, but are not limited to, benzoic acid,phenylacetic acid, salicylic acid, mandelic acid, phthalic acid,cynnamic acid, and the like.

Aliphatic ketones that may be used as solvents for veterinaryformulations are well known in the art and include, but are not limitedto, acetone, methyl ethyl ketone, methyl isobutyl ketone, methylisopropyl ketone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone,3-hexanone, and the like.

Aryl ethers that may be used include, but are not limited to, C₁-C₁₂alkyl-aryl ethers such as anisole and derivatives of anisole, ethylphenyl ether (phenetole), propyl phenyl ether, butyl phenyl ether, andthe like.

In still another embodiment of the third aspect of the invention, thesolvent of the stable formamidine compositions includesC₁-C₄-alkoxybenzene, C₁-C₁₀ carboxylic acid esters, phenyl carboxylicacid esters, carboxylic acid benzyl esters, C₁-C₆ saturated aliphaticketones, benzoic acid C₁-C₄ esters or mixtures thereof.

In other embodiments, the solvent includes methoxybenzene (4.33), butylacetate (5.0), benzyl acetate (5.0), methyl isobutyl ketone (13.1),ethyl benzoate (6.02), benzyl benzoate (4.8), octyl acetate or mixturesthereof. (Dielectric constants in parentheses)

In one embodiment, the solvent is a mixture of butyl acetate and anisoleor a mixture of butyl acetate and methyl isobutyl ketone.

In another embodiment of the invention, the solvent is octyl acetate. Inanother embodiment, the carrier comprises a mixture of octyl acetatewith another aprotic solvent or with a solvent having a dielectricconstant of about 2 to about 30. In a preferred embodiment, the solventwill be a polar aprotic solvent with a dielectric constant of about 2 toabout 30. In still another embodiment, the carrier comprises a mixtureof octyl acetate with one or more of butyl acetate, methyl isobutylketone or anisole.

In one embodiment of the invention, the [weight/volume]% solubility ofamitraz at room temperature in the solvent is from about 20% to about50%. In another embodiment, the [weight/volume]% solubility of amitrazat room temperature is from about 24% to about 46%. In still otherembodiments, the [weight/volume]% solubility of amitraz at roomtemperature in the solvent is from about 10% to about 60%, about 20% toabout 60%, or about 10% to about 50%.

A fourth aspect of the invention provides a formamidine composition(e.g. amitraz) with enhanced odor dissipation after application oradministration which comprises a veterinarily effective amount offormamidine and one or at least two aprotic solvents, preferably atleast two polar aprotic solvents, or at least two solvents each with adielectric constant of about 2 to about 30, including the solventsdescribed above. As used herein, enhanced odor dissipation refers to thefaster dissipation of the initial odor exhibited by the formulationwithin a period of time compared to the time required for dissipation ofodor by formulations of the prior art. For example, in one embodiment ofthe fifth aspect of the invention, the odor dissipation occurs withinabout 5 to about 25 minutes. In another embodiment, the odor dissipationoccurs within about 10 to about 15 minutes. In still another embodiment,the odor dissipation occurs within about 5 minutes to about 15 minutes,within about 10 minutes to about 25 minutes or within 15 minutes toabout 25 minutes. In comparison, formamidine formulations of the priorart exhibit an odor that does not dissipate within 25 minutes.

In other embodiments, the formamidine composition with enhanced odordissipation properties comprises one or more solvents with dielectricconstants of about 2 to about 20, about 5 to about 30, or about 10 toabout 30. More typically, the dielectric constant of the one or moresolvents will be between about 2 to about 15 or about 2 to about 10.

In other embodiments, the formamidine composition with enhanced odordissipation properties comprises one or more aprotic solvents,preferably one or more polar aprotic solvents, with dielectric constantsof about 2 to about 20, about 5 to about 30, or about 10 to about 30.More typically, the dielectric constant of the one or more polar aproticsolvents will be between about 2 to about 15 or about 2 to about 10.

In one embodiment, the one or at least two solvents that improve theodor dissipation of formamidine compositions include, but are notlimited to, an alkoxybenzene, carboxylic acid esters, aliphatic ketones,saturated aliphatic ketones, benzoic acid esters or mixtures thereof.

In another embodiment, the one or more solvents that improve the odordissipation of formamidine compositions include, but are not limited to,aryl ethers including alkoxybenzene compounds; carboxylic acid esters,including esters of aliphatic and aromatic carboxylic acids such asbenzoic acid esters, and compounds with multiple carboxylate groups;aliphatic ketones, cyclic ketones, or mixtures thereof.

In one embodiment, the one or at least two solvents that improve theodor dissipation of formamidine compositions includeC₁-C₄-alkoxybenzene, C₁-C₁₀ carboxylic acid esters, phenyl carboxylicacid esters, carboxylic acid benzyl esters, carboxylic acid phenylesters, benzyl carboxylic acid esters, C₁-C₆ saturated aliphaticketones, C₁-C₄ benzoic acid esters and mixtures thereof.

In additional embodiment of the invention, the formamidine compositionswith improved odor dissipation comprise one or at least two aproticsolvents each with a dielectric constant of about 2 to about 15including, but not limited to, methoxybenzene (4.33), butyl acetate(5.0), benzyl acetate (5.0), methyl isobutyl ketone (13.1), ethylbenzoate (6.02), benzyl benzoate (4.8), octyl acetate and mixturesthereof. (dielectric constants in parentheses)

In still other embodiments, the dielectric constant of the one or moresolvents is about 3 to about 10, about 3.5 to about 10, or about 4 toabout 6.5.

In a preferred embodiment, the solvent is octyl acetate.

In another preferred embodiment, the at least two solvents in theformamidine compositions with improved odor dissipation is a mixture ofbutyl acetate and anisole or a mixture of butyl acetate and methylisobutyl ketone.

A fifth aspect of the invention provides a composition for the treatmentand/or prevention of a parasitic infestation in an animal comprising atleast one (i.e. one or more) 1-arylpyrazole compound(s) and at least oneformamidine compound(s) in combination with one or more pharmaceuticallyor veterinarily acceptable carrier(s) and optionally a crystallizationinhibitor, wherein the 1-arylpyrazole compound (s) and the formamidinecompound (s) may be together in the same carrier or each active compoundmay be in a separate carrier.

In one embodiment, the one or more 1-arylpyrazole compound(s) are in afirst carrier and the formamidine compound(s) are in a second carrier,wherein the compounds and the first and second carriers arecompartmentalized separately from each other and are not in fluidcommunication before administration.

In another embodiment of the fifth aspect of the invention, the one ormore 1-arylpyrazole compound(s) and the formamidine compound(s) are inone common carrier.

It will be appreciated by those of skill in the art that the firstcarrier and the second carrier may be the same or different. Forexample, the first and second carriers may comprise the same solvent ormay include different solvents or combinations of solvents.

In one embodiment of the fifth aspect of the invention, the compositioncomprises:

(a) at least one 1-arylpyrazole compound of formula (IB):

in which:

R_(1b) is alkyl, CN or halogen;

R_(2b) is S(O)_(n)R_(14b) or 4,5-dicyanoimidazol-2-yl or haloalkyl;

R_(14b) is alkyl or haloalkyl;

R_(3b) is a hydrogen, halogen, —NR_(7b)R_(8b), —S(O)_(m)R_(9b),—C(O)R_(9b), —C(O)OR_(9b), alkyl, haloalkyl, —OR_(10b) or an—N═C(R_(11b))(R_(12b));

R_(6b) is a halogen, haloalkyl, haloalkoxy, S(O)_(q)CF₃ or SF₅ group;

R_(7B) and R_(8B) independently represent a hydrogen, alkyl, haloalkyl,—C(O)alkyl, —S(O)_(r)CF₃, acyl or alkoxycarbonyl; or

R_(7b) and R_(8b) can together form a divalent alkylene radical which isoptionally interrupted by one or two divalent heteroatoms;

R_(9b) is an alkyl or haloalkyl;

R_(10b) is hydrogen, alkyl or haloalkyl;

R_(11b) is hydrogen or alkyl radical;

R_(12b) is an optionally substituted aryl or an optionally substitutedheteroaryl group;

R_(4b) and R_(13b) represent, independently of one another, hydrogen,halogen CN or NO₂;

m, n, q and r represent, independently of one another, an integer equalto 0, 1 or 2;

Z represents a trivalent nitrogen atom or a C—R_(13b) radical, the threeother valencies of the carbon atom forming part of the aromatic ring;and

(b) at least one formamidine compound comprises at least one compound offormula (II):

wherein:

x is an integer from 0-5;

R₁₄ is alkyl, halogen or —OC(═O)NR_(a)R_(b),

-   -   wherein R_(a) and R_(b) are independently hydrogen or alkyl;

R₁₅ is hydrogen or alkyl;

R₁₆ is hydrogen or alkyl;

R₁₇ is hydrogen, alkyl or

(c) one or more veterinarily acceptable carrier(s); and

(d) optionally, at least one crystallization inhibitor.

In another embodiment of the fifth aspect of the invention, the1-arylpyrazole (s) is a compound of formula (IB), wherein

R_(1b) is methyl, CN or halogen;

R_(14b) is C₁-C₆-alkyl or C₁-C₆-haloalkyl;

R_(3b) is a hydrogen, halogen, —NR_(7b)R_(8b), —S(O)_(m)R_(9b),—C(O)R_(9b), —C(O)OR_(9b), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR_(10b) or—N═C(R_(11b))(R_(12b));

R_(7b) and R_(8b) independently represent a hydrogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl, —S(O)_(r)CF₃, C₁-C₆-acyl orC₁-C₆-alkoxycarbonyl radical; or

R_(7b) and R_(8b) may together form a divalent alkylene radical whichmay be interrupted by one or two divalent hetero atoms selected from thegroup consisting of oxygen or sulfur;

R_(9b) is a C₁-C₆-alkyl or C₁-C₆-haloalkyl radical;

R_(10b) is a C₁-C₆-alkyl or C₁-C₆-haloalkyl radical or a hydrogen atom;

R_(11b) is a C₁-C₆-alkyl radical or a hydrogen atom;

R_(12b) is an optionally substituted phenyl or optionally substitutedheteroaryl group wherein the substituents are selected from the groupconsisting of halogen, —OH, —O—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, cyano andC₁-C₆-alkyl;

R_(6b) is a halogen, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, S(O)_(q)CF₃ orSF₅ group; and

Z is a C—R_(13b) radical.

In another embodiment of the fifth aspect of the invention, the1-arylpyrazole(s) is a compound of formula (IB), wherein

R_(1b) is methyl, CN or halogen;

R_(2b) is S(O)_(n)R_(14b);

R_(14b) is C₁-C₆-alkyl or C₁-C₆-haloalkyl;

R_(3b) is —NR_(7b)R_(8b),

R_(7b) and R_(8b) independently represent a hydrogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl, —S(O)_(r)CF₃, C₁-C₆-acyl orC₁-C₆-alkoxycarbonyl radical;

R_(6b) is a halogen, C₁-C₆-haloalkyl, or C₁-C₆-haloalkoxy;

m, n, q and r represent, independently of one another, an integer equalto 0 or 1; and

Z is a C—R_(13b) radical.

In still another embodiment of the fifth aspect of the invention, the1-arylpyrazole(s) is a compound of formula (IB), wherein

R_(1b) is CN;

R_(2b) is S(O)_(n)R_(14b);

R_(14b) is CF₃;

R_(3b) is NR_(7b)R_(8b);

R_(7b) and R_(8b) are hydrogen;

R_(4b) and R_(13b) are each Cl;

R_(6b) is CF₃.

(this compound is also known as fipronil or1-[2,6-dichloro-4-trifluoromethylphenyl]-3-cyano-4-trifluoromethylsulfinyl-5-amino pyrazole).

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one formamidine compound and at least one1-arylpyrazole of formula (I) as described above, one or morepharmaceutically acceptable carrier(s), and optionally one or morecrystallization inhibitors.

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one formamidine compound of formula (II)described above and at least one 1-arylpyrazole compound of formula (I)described above, one or more pharmaceutically acceptable carrier(s), andoptionally one or more crystallization inhibitors.

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one 1-arylpyrazole of formula (I) whereinR₁ is cyano, —C(O)R₈, —C(O)OR₈, —C(O)NR₉R₁₀, —C(═NOH)NH₂, —C(═NNH₂), or—C(S)NH₂.

In another embodiment of the formulation, the 1-arylpyrazole(s) offormula (I) is provided wherein R₃ is alkyl or haloalkyl.

In one embodiment of the fifth aspect of the invention, the formulationcomprises a 1-arylpyrazole(s) of formula (I) wherein:

R₁ is cyano, —C(O)R₈, —C(O)OR₈, —C(O)NR₉R₁₀, —C(═NOH)NH₂, —C(═NNH₂), or—C(S)NH₂; and

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R₁₁.

In another embodiment of the formulation, the 1-arylpyrazole(s) offormula (I) is provided wherein:

R₁ is cyano, —C(O)R₈, —C(O)OR₈, —C(O)NR₉R₁₀, —C(═NOH)NH₂, —C(═NNH₂), or—C(S)NH₂;

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R₁₁; and

R₃ is alkyl or haloalkyl.

In still another embodiment of the fifth aspect of the invention, the1-arylpyrazole(s) of formula (I) is provided wherein:

R₁ is cyano;

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R₁₁;

R₃ is alkyl or haloalkyl;

R₄, R₅ and R₇ are independently hydrogen, or halogen; and

Z is C—R₁₃.

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one 1-arylpyrazole(s) of formula (I) isprovided wherein:

R₁ is cyano;

R₂ is —SCN, 4-5-dicyanoimidazol-2-yl, or —S(O)_(m)R_(1l);

R₃ is C₁-C₄alkyl or C₁-C₄haloalkyl;

R₆ is halogen, haloalkyl or SF₅; and

Z is C—R₁₃.

In one embodiment of the fifth aspect of the invention, the formulationcomprises at least one 1-arylpyrazole(s) of formula (I) wherein:

R₁ is cyano;

R₂ is —S(O)_(m)R₁₁;

R₃ is C₁-C₄alkyl, C₁-C₄haloalkyl, or NR₉R₁₀;

R₄, R₅ and R₇ are independently hydrogen, or halogen;

R₆ is halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, or SF₅;

Z is C—R₁₃; and

R₁₃ is halogen or C₁-C₄haloalkyl.

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one 1-arylpyrazole of formula (I)wherein:

R₁ is cyano;

R₂ is —S(O)_(m)R₁₁;

R₃ is methyl, ethyl, propyl, or C₁-C₄haloalkyl;

R₄ is halogen;

R₅ and R₇ are hydrogen;

R₆ is C₁-C₄haloalkyl;

Z is C—R₁₃;

R₁₁ is —CF₃, —CClF₂, or CFCl₂; and

R₁₃ is halogen.

In still another embodiment of the fifth aspect of the invention, theformulation comprises at least one 1-arylpyrazole of formula (I)wherein:

R₁ is cyano;

R₂ is —S(O)_(m)R₁₁;

R₃ is methyl or ethyl;

R₄ is chloro or fluoro;

R₅ and R₇ are hydrogen;

R₆ is —CF₃;

Z is C—R₁₃;

R₁₁ is —CFCl₂; and

R₁₃ is chloro or fluoro.

In another embodiment of the fifth aspect of the invention theformulation comprising at least one 1-arylpyrazole and at least oneformamidine compound comprises at least one 1-arylpyrazole of formula(IA) as described above, or a salt thereof, a pharmaceutically orveterinarily acceptable carrier, and optionally at least onecrystallization inhibitor.

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one formamidine of formula (II) describedabove and at least one 1-arylpyrazole compound of formula (IA) describedabove, or salts thereof, a pharmaceutically or veterinarily acceptablecarrier, and optionally at least one crystallization inhibitor.

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one 1-aryl-5-alkyl pyrazole compound offormula (IA) wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl, or ethyl;

R_(4a) is halogen;

R_(6a) is C₁-C₄ haloalkyl;

R_(13a) is halogen;

R_(11a) is —CF₃, —CClF₂, or —CFCl₂; and

m is 0, 1 or 2.

In another embodiment of the fifth aspect of the invention, theformulation comprises at least one 1-aryl-5-alkyl pyrazole compound offormula (IA) wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl, or ethyl;

R_(4a) is halogen;

R_(6a) is C₁-C₄ haloalkyl;

R_(13a) is halogen;

R_(11a) is —CF₃, —CClF₂, or —CFCl₂; and

m is 0, 1 or 2.

In still another embodiment of the fifth aspect of the invention, thecompound(s) of formula (IA) is a compound wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl;

R_(4a) is —Cl;

R_(6a) is —CF₃;

R_(13a) is —F;

R_(11a) is —CFCl₂; and

m is 0, 1 or 2.

In still another embodiment of the fifth aspect of the invention, theformamidine compound(s) in the formulation is a compound of formula(II), wherein

x is an integer from 1 to 3;

R₁₄ is C₁-C₄ alkyl, fluoro, chloro or bromo or —OC(═O)NR_(a)R_(b),

-   -   wherein R_(a) and R_(b) are independently hydrogen or C₁-C₄        alkyl;

R₁₅ is hydrogen or C₁-C₄ alkyl;

R₁₆ is hydrogen or C₁-C₄ alkyl;

R₁₇ is hydrogen, C₁-C₄ alkyl; or

In another embodiment, the formamidine compound(s) is a compound offormula (II), wherein

x is an integer from 1 to 2;

R₁₄ is methyl, chloro or —OC(═O)NR_(a)R_(b),

-   -   wherein R_(a) is hydrogen and R_(b) is methyl;

R₁₅ is hydrogen or methyl;

R₁₆ is hydrogen or methyl;

R₁₇ is hydrogen, methyl; or

In a further embodiment of the fifth aspect of the invention, theformamidine compound(s) is selected from the group consisting of:

and mixtures thereof.

In another embodiment of the fifth aspect of the invention, theformamidine compound is:

In a preferred embodiment of the fifth aspect of the invention, the1-arylpyrazole is fipronil and the formamidine compound is amitraz.

In another preferred embodiment of the fifth aspect of the invention,the 1-arylpyrazole compound(s) is in one carrier system and theformamidine compound(s) is in a separate second carrier system.

A sixth aspect of the invention provides composition for the treatmentand prevention of parasites in an animal in need thereof whichcomprises:

(a) at least one formamidine compound of formula (II):

wherein:

x is an integer from 0-5;

R₁₄ is alkyl, halogen or —OC(═O)NR_(a)R_(b),

-   -   wherein R_(a) and R_(b) are independently hydrogen or alkyl;

R₁₅ is hydrogen or alkyl;

R₁₆ is hydrogen or alkyl;

R₁₇ is hydrogen, alkyl or

and

(b) a veterinarily acceptable carrier.

In one embodiment of the sixth aspect of the invention, theformamidine(s) of formula (II) is provided wherein:

R₁₄ is C₁-C₄alkyl or halogen;

R₁₅ is hydrogen or C₁-C₄alkyl; and

R₁₆ is hydrogen or C₁-C₄alkyl.

In another embodiment of the sixth aspect of the invention,formamidine(s) of formula (II) is provided wherein R₁₇ is

In still another embodiment, the formulation comprises formamidinecompound(s) wherein:

x is an integer from 1, 2 or 3;

R₁₄ is C₁-C₄alkyl, halogen or —OC(═O)NR_(a)R_(b),

-   -   wherein R_(a) and R_(b) are independently hydrogen or        C₁-C₄alkyl;

R₁₅ is hydrogen or C₁-C₄alkyl;

R₁₆ is hydrogen or C₁-C₄alkyl;

R₁₇ is hydrogen, C₁-C₄alkyl or

In another embodiment of the sixth aspect of the invention, thecomposition has enhanced odor dissipation following application oradministration.

In a still another embodiment of the sixth aspect of the invention, thecomposition has enhanced stability compared to compositions comprisingformamidines of the prior art.

In a another embodiment of the sixth aspect of the invention, thecomposition comprises one or at least two aprotic solvents each with adielectric constant of about 2 to about 30.

In a preferred embodiment, the composition comprises octyl acetate.

In another preferred embodiment of the sixth aspect of the invention,the composition comprises at least two solvents in a mixture of butylacetate and anisole or a mixture of butyl acetate and methyl isobutylketone.

In another preferred embodiment of the sixth aspect of the invention,the formamidine compound (a) is amitraz.

Methods of Treatment

In an seventh aspect of the invention, a method for preventing ortreating a parasite infestation/infection in an animal is provided,comprising administering a composition comprising an effective amount ofat least one 1-arylpyrazole compound of formula (I), (IA) or (IB)together with a pharmaceutically or veterinarily acceptable carrier andoptionally a crystallization inhibitor. The compositions or formulationsof the invention have long-lasting efficacy against fleas and ticks andare also able to quickly eradicate flea and tick infestations.

By “treating” or “treat” or “treatment” is intended the application oradministration of a composition of the invention to an animal that has aparasitic infestation for the eradication of the parasite or thereduction of the number of the parasites infesting the animal undergoingtreatment. It is noted that the compositions of the invention may beused to prevent such a parasitic infestation.

In one embodiment, a formulation comprising a 1-arylpyrazole compound offormula (IA) has an efficacy of about 90% or greater against fleas 30days after application. In another embodiment, a formulation comprisinga 1-arylpyrazole compound of formula (IA) has an efficacy of about 99%or greater against fleas 51 days or 58 days after application.

In still another embodiment, a formulation comprising a 1-arylpyrazolecompound of formula (IA) has an efficacy of about 85% or greater againstticks 23 days after application. In yet another embodiment, aformulation comprising a 1-arylpyrazole compound of formula (IA) has anefficacy of about 90% or greater against ticks 44 days or 58 days afterapplication. In still another embodiment, a formulation comprising a1-arylpyrazole compound of formula (IA) has an efficacy of about 99% orgreater against ticks 58 days after application.

In another embodiment, a formulation comprising a 1-arylpyrazole offormula (IA) is able to eradicate a flea infestation (as tested in theexamples herein) more quickly than 1-arylpyrazole compounds of the priorart. In an embodiment, the 1-arylpyrazole compound is able to eradicatea flea infestation in less than 10 hours or less than 9 hours afterapplication.

In another embodiment, a formulation comprising a 1-arylpyrazole offormula (IA) is able to eradicate a tick infestation (as tested in theexamples herein) in less than 20 hours after application.

In one embodiment, the invention provides a method for preventing ortreating an ectoparasitic infestation/infection in an animal. In anotherembodiment, the invention provides a method for preventing or treatingan endoparasitic infestation/infection in an animal. In certainembodiments for treating an endoparasitic infestation, the compositionsof the invention may include an additional anthelmintic agent.

In one embodiment of the method, the composition comprising the1-arylpyrazole compound (s) and the carrier exhibits enhanced stabilityand/or enhanced efficacy.

An eighth aspect of the invention provides a method for treating orpreventing a parasite infestation in an animal in need thereofcomprising administering an effective amount of a composition of theinvention that comprises at least one 1-arylpyrazole compound, at leastone formamidine compound or at least one formamide compound, orcombinations thereof, and optionally at least one crystallizationinhibitor; wherein the 1-arylpyrazole is administered in a first carrierand the formamidine compound is administered in a second carrier, andwherein the first carrier is isolated from the second carrier and not influid communication with the second carrier within the administrationdevice.

In one embodiment of the eighth aspect of the invention, the1-arylpyrazole compound (s) is a compound of formula (I), (IA) or (IB).In another embodiment of the eighth aspect of the invention, theformamidine compound (s) is a formamidine compound of formula (II).

It will be appreciated by those of skill in the art that the method ofthe invention encompasses administering the 1-arylpyrazole compound(s)separately from the formamidine compound as well as administering the1-arylpyrazole compound(s) together with the formamidine compound(s),although the two compounds may be in separate carriers. For example, the1-arylpyrazole compound(s) may be administered at the same location onthe animal as the formamidine compound(s) or the 1-arylpyrazolecompound(s) may be administered at a different location on the animal.Furthermore, the 1-arylpyrazole compound(s) may be administered by onemode of administration (e.g. topical, oral, parenteral, etc.) while theformamidine compound(s) may be administered by a different mode ofadministration. The method of the invention also encompasses theadministration of the 1-arylpyrazole compound(s) simultaneously with theformamidine compound(s) or sequentially with the formamidine compound(s)(i.e. at different times).

In one embodiment, the first carrier comprises a first solvent systemand the second carrier comprises a second solvent system that isdifferent from the first solvent system.

In one embodiment of the eighth aspect of the invention, the methodcomprises administering the 1-arylpyrazole (s) separately from theformamidine compound(s).

In another embodiment, the 1-arylpyrazole (s) is administeredsimultaneously with the formamidine compound(s).

In yet another embodiment of the eighth aspect of the invention, thearylpyrazole(s) is administered separately and simultaneously with theformamidine compound(s).

In a ninth aspect of the invention, a method for preventing or treatinga parasite infestation in an animal is provided, comprisingadministering an effective amount of at least one 1-arylpyrazolecompound and an effective amount of at least one formamidine orformamide compound to the animal in need thereof, wherein the compoundsare administered via a multiple-cavity container, wherein a first cavityis used to store the veterinarily effective amount of one or moreformamidine compounds, formamide compounds, or mixtures thereof, in afirst veterinarily acceptable carrier and administer the composition tothe animal therefrom; and wherein a second cavity is used to store theveterinarily effective amount of a 1-arylpyrazole compound in a secondveterinarily acceptable carrier and administer the composition to theanimal therefrom. The multiple cavity container may have two or morecavities, that may contain different active agents and differentcarriers. Alternatively, the multiple cavity containers may be used toinclude multiple doses of the same active agent for easy administration.In one embodiment, the multiple cavity container is a dual-cavitycontainer. Other embodiments include multiple cavity containers withthree, four, or more cavities. As discussed below, the multiple cavitycontainers will comprise delivery ports for administering thecompositions.

In one embodiment, the multiple cavity container is a dual cavitycontainer that comprises:

a first cavity defined by a front wall and a divider wall; and

a second cavity defined by a rear wall the divider wall;

wherein the first cavity is used to store and administer a veterinarilyeffective amount of at least one formamidine compounds, at least oneformamide compounds, or mixtures thereof; and wherein the second cavityis used to store and administer a veterinarily effective amount of atleast one 1-arylpyrazole compound.

In one embodiment of the ninth aspect of the invention, an effectiveamount of the active compounds of the invention are administered via adual-cavity container comprising:

a first cavity defined by a front wall and a divider wall;

a second cavity defined by a rear wall and a divider wall;

wherein a veterinarily effective amount of at least one 1-arylpyrazolecompound is administered via the first cavity; and wherein aveterinarily effective amount of at least one formamidine compound isadministered via the second cavity.

In another embodiment of the ninth aspect of the invention, a method isprovided wherein an effective amount of fipronil is administered via afirst cavity of a multiple-cavity container and an effective amount of aformamidine compound is administered via a second cavity of amultiple-cavity container.

In still another embodiment of the ninth aspect of the invention, amethod is provided wherein an effective amount of a 1-arylpyrazolecompound of formula (I), (IA) or (IB) is administered via a first cavityof a dual-cavity container, and an effective amount of a formamidine offormula (II) is administered via a second cavity of a dual cavitycontainer.

In still another embodiment of the ninth aspect of the invention, amethod is provided wherein an effective amount of fipronil isadministered to the animal via a first cavity of a dual-cavitycontainer, and an effective amount of amitraz is administered via asecond cavity of a dual-cavity container.

In yet another embodiment of the ninth aspect of the invention, a methodis provided wherein an effective amount of a 1-arylpyrazole compound offormula (IA) is administered to the animal via a first cavity of adual-cavity container, and an effective amount of amitraz isadministered via a second cavity of a dual-cavity container.

Other dual chamber dispensers which can be incorporated into theinvention include but are not limited to the dispensers referred to inU.S. Pat. Nos. 5,318,203; 5,353,961; 6,161,729; 6,230,935, 6,883,295 andU.S. Design Ser. No 404,972, the disclosures of which are herebyincorporated by reference in their entirety.

In some embodiments, a composition of the invention may be deliveredfrom a container having two or more cavities. Each cavity may include acomponent of the composition. For example, a container may include twodistinct cavities, three distinct cavities or more. Each cavity mayinclude one or more components of the composition, which may be in thesame or different carriers. This aspect of the invention allows for theadministration of combination of active compounds that may not becompatible together in the same carrier, or for the administration ofcompounds that require different carriers and/or excipients to providesufficient stability and/or efficacy.

As discussed above, it has been found that formulations comprising botha 1-arylpyrazole compound and a formamidine compound present together incertain carriers may not have sufficient storage shelf lives. Such asituation is problematic for commercial products that may be stored atambient conditions for extended periods of time (months to years).Therefore, the compositions and methods of the invention that providefor the administration of a 1-arylpyrazole compound and a formamidinecompound via a dual cavity container are particularly useful becausethey allow the administration of highly efficacious compositions fortreating parasitic infestations and also provide for an extended storageshelf life.

As shown in FIG. 1 some embodiments of the dual-cavity container mayinclude container 10 having thermoformed dual cavities, upper cavity 12and lower cavity 14. Container 10 may include front wall 16, rear wall18, and divider wall 20 which may define the cavities of the container.For example, as shown in FIG. 1, the front wall, rear wall and dividerwall define a dual-cavity container.

In some embodiments, divider wall 20 may be thinner than either frontwall 16 or rear wall 18. For example, divider wall 20 may have athickness in a range from about 5% to about 80% of either of the rearwall or front wall. Some embodiments may include a divider wall having athickness in a range from about 20% to about 70% of either the rear wallor the front wall. Typically, the divider wall will have a thickness offrom about 30% to about 70% or from about 40% to about 60% of either thefront or rear wall. In another embodiment, the divider wall has athickness of about 10% to about 40% of either of the rear wall or frontwall. Alternately, some embodiments may include a divider wall having athickness greater than a front wall, a rear wall and/or both the frontand rear walls.

The front wall and the rear wall may be constructed from materialsincluding, but not limited to films, rigid monolayers, laminate rigidfilms and/or any materials known in the art. For example, suitablematerials include, but are not limited to, polyethylene terephthalate(PET), amorphous polyethylene terephthalate (APET), polyethyleneterephthalate glycol (PETG) or crystalline polyethylene terephthalate(CPET), polyvinyl chloride (PVC), polypropylene (PP) polyethylene (PE),polyamide (PA), cycloolefin copolymers such as those known under thetradename COC®, poly acrylonitrile (PAN) such as known under thetradename BAREX®, and fluoropolymer or poly chlorotrifluoroethylene(PCTFE such as that as known under the tradename ACLAR®.

The divider wall may be constructed from materials including, but notlimited to barrier films, flexible monolayers, laminate flexible filmsand/or any materials known in the art. For example, it includespolyester (PET), polypropylene (PP) polyethylene (PE), ethyl vinylalcohol (EVOH), ethyl vinyl acetate (EVA), polyamide (PA), polyacrylonitrile (PAN) such as known under the tradename BAREX®,fluoropolymer or poly chlorotrifluoroethylene (PCTFE such as that asknown under the tradename ACLAR® and aluminium foil. Preferably, thealuminium foil has a thickness of less than 60 μm.

U.S. Pat. No. 6,260,735 to Fuquen, and Published InternationalApplication WO 2001/087736, both incorporated herein by reference intheir entirety, describes combinations of suitable construction materialfor dual chamber sachet. These materials are also suitable for themultiple cavity containers of the present application. In particular,this publication describes that suitable combinations of materials ofconstruction for the front and rear wall including PET/AluminumFoil/polyacrylonitriie (BAREX®), PET/Aluminum Foil/low densitypolyethylene (LDPE), Bi-Orientated polypropylene (BOPP)/AluminumFoil/BAREX®, BOPP/Aluminum Foil/LDPE and LDPE/ethylene-vinyl alcoholpolymer (EVOH)/LDPE, PET/EVOH/LDPE, BOPP/EVOH/LPDE, LPDE Based Monolayeror Polyefins Blend, Sealable PET Based Monolayer, PET/PE/Sealable PET,PET/Foil/Sealable PET, Nylon/Foil/PE, and Nylon/PE/Sealable PET.

In addition to the material combinations described above, other suitablecombinations of construction materials for the multiple containers ofthe invention include, but are not limited to, PP/PE and PP/PE-EVOH-PEand PP/PP and PP/BAREX® and COC®/PE and COC®/PE-EVOH-PE and COC®/PP andCOC/BAREX® and ACLAR®/APET/PE and ACLAR®/APET/PE-EVOH-PE andACLAR®/APET/PP and ACLAR®/APET/BAREX® and ACLAR®/PETG/PE andACLAR®/PETG/PE-EVOH-PE and ACLAR®/PETG/PP/and ACLAR®/PETG/BAREX® andACLAR®/PVC/PE and ACLAR®/PVC/PE-EVOH-PE and ACLAR®/PVC/PP andACLAR®/PVC/BAREX®.

For the divider wall U.S. Pat. No. 6,260,735 describes the followingmaterial combinations: LPDE Based Or Polyefins Blend Monolayer, BAREX®Monolayer, LDPE/Aluminum Foil/LDPE, BAREX®/Aluminum Foil/BAREX®LDPE/EVOH/LDPE, Sealable PET/PE/Sealable PET, Sealable PET/Foil/SealablePET, and PE/Nylon/PE. Additional combinations of materials suitable forthe divider wall of the container of the present invention include, butare not limited to, PE-EVOH-PE:Alu foil/PE-EVOH-PE andPE-EVOH-EVA-PE/Alu foil/PE-EVA-EVOH-PE and PP/Alu foil/PP and PP/PE/Alufoil/PE/PP and PE/ACLAR®/PE and PP/ACLAR®/PP and BAREX®/ACLAR®/BAREX®and PE-EVOH-PE/PA/PE-EVOH-PE.

The walls may be coupled along a part of their perimeter to define thecavities. For example, the walls may be bonded together along theperimeter.

FIG. 1 depicts upper cavity 12 and lower cavity 14 having substantiallythe same proximal ends 22 and distal ends 24. Alternately, someembodiments may include ends which vary. For example, FIG. 2 shows uppercavity 12 being shorter at distal end 24 than distal end 24′ of lowercavity 14.

As shown in FIGS. 1-4, cavities 12, 14 may have different volumes. Forexample, FIG. 2 depicts upper cavity 12 having a smaller volume thanlower cavity 14.

In some embodiments, a multi-cavity container may be used to deliver aliquid, a paste, a cream, powder, and/or granules. Multi-cavitycontainers may be to deliver drugs, cosmetics, food, household supplies,shampoos, conditioners, detergent, and/or adhesives. In an alternateembodiment, two or more components may be delivered by squeezing orpressing the external wall of the multi-cavity container. The componentsin the cavities may differ. For example, in FIGS. 1-4, upper cavity 12may include a component which differs from lower cavity 14. In alternateembodiments, upper cavity 12 and lower cavity 14 may includesubstantially similar components.

As shown in FIG. 2, container 10 may include indenture 26. Indenture 26may be positioned to allow for uniform delivery of the components. Forexample, indenture 26 may positioned on front wall 16 defining uppercavity 12. In some embodiments, there may be an indent positioned onboth the front and rear walls. Indentures may be shaped to conform to afinger. Indentures may also be shaped to conform to a thumb. In someembodiments, indentures may allow for improved gripping.

Container 10 may include transparent external walls. In someembodiments, the front and rear walls may be configured to allow foraccurate and full squeezing. In some embodiments, a multi-cavitycontainer may be configured to dispense without any tilt, bend, and/ormovement after opening.

FIG. 5 depicts opening mechanism 28. Opening mechanism 28 may includebut is not limited to a fracture line 32, a die cut, a perforation orany other design known in the art. In some embodiments as shown in FIG.5, opening mechanism may be a die cut. Opening mechanism 28 may includeone half moon shape 31. For example, a half moon shaped die cut may bemade. In some embodiments, two half moon shaped die cuts 31 and 31′ maybe made perpendicular to a fracture line 32.

Alternately, an opening mechanism may have any geometry including butnot limited to a line, a curve, or any geometry known in the art. Theopening mechanism may tear a divider wall with no elongation. Further,the opening mechanism may be configure so that there are no sharp edgesto the standard perpendicular connection between fracture line andperimeter of rigid front/rear walls. For example, FIG. 6 depicts openingmechanism 28 as a line. As shown in FIGS. 6-8, some embodiments mayinclude tip 30 which may be twisted off along opening mechanism 28.

In some embodiments, a multi-cavity container may be configured todispense without any tilt, bend, and/or movement after opening.

Some embodiments may include marks to position front and rear wallsprior to coupling. For example, materials for the construction of thewalls may be preprinted with a printing mark to customize each side withperfect positioning.

As shown in FIG. 7, a strip of containers may be connected prior to use.

A container may be constructed from a central ribbon for the dividerwall and an external ribbon for the front and rear walls. Athermoforming station may form the front and rear walls prior to afeeding station delivering the central ribbon. Then, the wall perimetersmay be coupled together, for example, by bonding or welding. Thethermoforming process is a very well known process, and has beendescribed in U.S. Pat. Nos. 5,223,073, 6,883,295, and in InternationalApplication Publication Nos. WO 2004/069658 A2, WO 2005/094330 and WO2008/065512, all incorporated herein by reference in their entirety. Inaddition, some embodiments may include a cooling period in thethermoforming station prior to coupling the wall perimeters.

Some embodiments may include positioning the central ribbon to extendbeyond the external ribbon. Positioning the ribbons in this manner mayensure a complete seal between the cavities.

A tenth aspect of the invention is a kit for the treatment or preventionof a parasitic infestation in an animal, comprising one or more1-arylpyrazole compound(s) in a first veterinarily acceptable carrier,one or more formamidine compound(s) in a second veterinarily acceptablecarrier, and a multiple cavity container; wherein the one or more1-arylpyrazole compound(s) in a first veterinarily acceptable carrier isin a first cavity of the multiple cavity container and the one or moreformamidine compound(s) in a second veterinarily acceptable carrier isin a second cavity of the multiple cavity container; and wherein thefirst cavity is defined by a front wall and a divider wall; and thesecond cavity defined by a rear wall the divider wall.

As discussed above, it has been surprisingly been found thatcompositions comprising formamidine compounds in combination with some1-arylpyrazole compounds in certain solvent carriers do not havesufficient storage shelf lives for commercial use. The inventive kitdescribed herein allow for the long term storage and subsequentadministration of compositions comprising 1-arylpyrazoles andformamidines. Furthermore, certain synergistic compositions of1-arylpyrazoles and amitraz may be stored and administered using the kitwithout degradation for long periods of time, allowing for the superiorcontrol of parasites in animals.

The kit may include any of the 1-arylpyrazle compositions describedabove in one or more of the cavities, including any of the veterinarilyacceptable carriers previously described.

In one embodiment, the first veterinarily acceptable carrier that iscombined with the 1-arylpyrazole compound(s) includes, but is notlimited to, C₁-C₁₀ alcohols or esters thereof (including acetates, suchas ethyl acetate, butyl acetate and the like), C₁₀-C₁₈ saturated fattyacids or esters thereof, C₁₀-C₁₈ monounsaturated fatty acids or estersthereof, monoesters or diesters of aliphatic diacids, glycerolmonoesters (e.g. monoglycerides), glycerol diesters (e.g. diglycerides),glycerol triesters (e.g. triglycerides such as triacetin), glycols,glycol ethers, glycol esters or glycol carbonates, polyethylene glycolsof various grades (PEGs) or monoethers, diethers, monoesters or diestersthereof (e.g. diethylene glycol monoethyl ether), or mixtures thereof.

In another embodiment, the first veterinarily acceptable carrierincludes, but is not limited to, acetone, acetonitrile, benzyl alcohol,ethanol, isopropanol, diisobutyl adipate, diisopropyl adipate (alsoknown as CERAPHYL 230), butyl diglycol, dipropylene glycol n-butylether, ethylene glycol monoethyl ether, ethylene glycol monomethylether, dipropylene glycol monomethyl ether, liquid polyoxyethyleneglycols, propylene glycol monomethyl ether, propylene glycol monoethylether, 2-pyrrolidone including N-methylpyrrolidone, diethylene glycolmonoethyl ether, triacetin, butyl acetate, octyl acetate, propylenecarbonate, butylene carbonate, dimethyl sulfoxide, amides includingdimethylformamide and dimethylacetamide, or any combination thereof.

In another embodiment, the second veterinarily acceptable carrierincludes, but is not limited to, aryl ethers including alkoxybenzenecompounds; carboxylic acid esters, including aliphatic and aromaticcarboxylic acids such as benzoic acid esters, and compounds withmultiple carboxylate groups; aliphatic ketones, saturated aliphaticketones, cyclic ketones, or mixtures thereof.

In yet another embodiment, the second veterinarily acceptable carrierincludes, but is not limited to, C₁-C₁₀ carboxylic acid esters, phenylcarboxylic acid esters, carboxylic acid benzyl esters, benzoic acidC₁-C₄ alkyl esters, C₁-C₆ saturated aliphatic ketones, and mixturesthereof.

In still another embodiment, the second veterinarily acceptable carrierincludes, but is not limited to, methoxybenzene, butyl acetate, benzylacetate, methyl isobutyl ketone, ethyl benzoate, benzyl benzoate, octylacetate or mixtures thereof.

In another embodiment, the second veterinarily acceptable carrierincludes one or more solvent(s) with a dielectric constant of about 2 toabout 30. In other embodiments of the invention, the second veterinarilyacceptable carrier comprises a solvent with a dielectric constant ofabout 2 to about 40, 2 to about 20, 5 to about 30, or 10 to about 30.

In still other embodiments, the second veterinarily acceptable carriercomprises one or more solvents with a dielectric constant of about 2 toabout 15 or about 3 to about 10. In still another embodiment, thedielectric constant of the one or more solvents is about 3.5 to about10. In another embodiment, the dielectric constant of the one or moresolvents is about 4 to about 6.5.

In another embodiment, the second veterinarily acceptable carrierincludes one or more aprotic solvents, preferably polar aproticsolvents, with dielectric constants of about 2 to about 30. In otherembodiments of the invention, the second veterinarily acceptable carriercomprises one or more aprotic solvent(s) with a dielectric constant ofabout 2 to about 40, 2 to about 20, 5 to about 30, or 10 to about 30.

In still other embodiments, the second veterinarily acceptable carriercomprises one or more aprotic solvent(s) with a dielectric constant ofabout 2 to about 15 or about 3 to about 10. In still another embodiment,the dielectric constant of the one or more aprotic solvent(s) is about3.5 to about 10. In another embodiment, the dielectric constant of theone or more aprotic solvent(s) is about 4 to about 6.5. In somepreferred embodiments, the solvents will be polar aprotic solvents withdielectric constants in the ranges described above.

In another embodiment, the solvent(s) with a dielectric constants ofabout 2 to about 30 comprised by the second veterinarily acceptablecarrier will contain less than about 0.5% or less than about 0.3% (w/w)water. In other embodiments, the solvent with a dielectric constant ofabout 2 to about 30 will typically contain less than 0.2% (w/w) water.Preferably, the solvent will contain less than about 0.1%, or less thanabout 0.05% or less than about 0.025% (w/w) water. In other embodiments,the solvent will contain from about 0.0001% (w/w) to about 0.5% (w/w)water. More typically, the solvent with a dielectric constant of about 2to about 30 will contain about 0.0001% to about 0.3%, about 0.001% toabout 0.3%, about 0.001% to about 0.1% or about 0.001% to about 0.05%(w/w) water. Preferably, the solvent will contain from about 0.001% toabout 0.025% (w/w) water.

The compositions of the invention can be in a variety of forms suitablefor different forms of administration including, but are not limited to,oral formulations, injectable formulations, and topical, dermal orsubdermal formulations.

The compositions of the invention may be in a form suitable for oraluse, for example, as baits (see, e.g., U.S. Pat. No. 4,564,631,incorporated herein by reference), dietary supplements, troches,lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueousor oily suspensions, aqueous or oily solutions, oral drenchformulations, dispersible powders or granules, syrups or elixirs,enteric formulations or pastes. Compositions intended for oral use maybe prepared according to any method known in the art for the manufactureof pharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,bittering agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc, the tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874, which are incorporated herein by reference intheir entirety, to form osmotic therapeutic tablets for controlledrelease.

Formulations for oral use may be hard gelatin capsules, wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin. Capsules may also besoft gelatin capsules, wherein the active ingredient is mixed with wateror miscible solvents such as propylene glycol, PEGs and ethanol, or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase maybe a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monoleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment of the formulation, the composition of the inventionis in the form of a microemulsion. Microemulsions are well suited as theliquid carrier vehicle. Microemulsions are quaternary systems comprisingan aqueous phase, an oily phase, a surfactant and a cosurfactant. Theyare translucent and isotropic liquids. Microemulsions are composed ofstable dispersions of microdroplets of the aqueous phase in the oilyphase or conversely of microdroplets of the oily phase in the aqueousphase. The size of these microdroplets is less than 200 nm (1000 to100,000 nm for emulsions). The interfacial film is composed of analternation of surface-active (SA) and co-surface-active (Co-SA)molecules which, by lowering the interfacial tension, allows themicroemulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase can be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase comprises oftriglycerides. In another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. Another embodiment of the oily phase willrepresent a % v/v range selected from the group consisting of about 2 toabout 15%; about 7 to about 10%; and about 8 to about 9% v/v of themicroemulsion.

The aqueous phase includes, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment of the glycol derivatives, the glycol isselected from the group consisting of propylene glycol, diethyleneglycol monoethyl ether, dipropylene glycol monoethyl ether and mixturesthereof. Generally, the aqueous phase will represent a proportion fromabout 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion include diethylene glycol monoethylether, dipropyelene glycol monomethyl ether, polyglycolyzed C₈-C₁₀glycerides or polyglyceryl-6 dioleate. In addition to these surfactants,the cosurfactants include short-chain alcohols, such as ethanol andpropanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and cosurfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same formulation. In one embodiment for the amount ofsurfactant/cosurfactant, the cosurfactant to surfactant ratio will befrom about 1/7 to about 1/2. In another embodiment for the amount ofcosurfactant, the ratio will be from about 25 to about 75% v/v ofsurfactant and from about 10 to about 55% v/v of cosurfactant in themicroemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, atachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and/or coloring agent(s).

In another embodiment of the invention, the composition can be in pasteform. Examples of embodiments in a paste form include but are notlimited to those described in U.S. Pat. Nos. 6,787,342 and 7,001,889,both of which are incorporated herein by reference. In addition to theactive agent of the invention, the paste can also contain fumed silica;a viscosity modifier; a carrier; optionally, an absorbent; andoptionally, a colorant, stabilizer, surfactant, or preservative.

The process for preparing a paste formulation comprises the steps of:

(a) dissolving or dispersing the active agent into the carrier bymixing;

(b) adding the fumed silica to the carrier containing the dissolvedactive agent compound and mixing until the silica is dispersed in thecarrier;

(c) allowing the intermediate formed in (b) to settle for a timesufficient in order to allow the air entrapped during step (b) toescape; and

(d) adding the viscosity modifier to the intermediate with mixing toproduce a uniform paste.

The above steps are illustrative, but not limiting. For example, step(a) can be the last step.

In one embodiment of the formulation, the formulation is a pastecontaining the active agent compound, fumed silica, a viscositymodifier, an absorbent, a colorant; and a hydrophilic carrier which is atriacetin, a monoglyceride, a diglyceride, or a triglyceride. The pastemay also include a viscosity modifier including, but is not limited to,PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine,glycerol, propylene glycol, polyoxyethylene (20) sorbitan mono-oleate(polysorbate 80 or Tween 80), or polyoxamers (e.g., Pluronic L 81); anabsorbent including, but not limited to, magnesium carbonate, calciumcarbonate, starch, or cellulose and its derivatives.

Colorants may be added to the inventive formulations. Colorantscontemplated by the present invention are those commonly known in theart. Specific colorants include, for example, dyes, FD&C Blue #1Aluminum Lake, caramel, colorant based upon iron oxide or a mixture ofany of the foregoing. Especially preferred are organic dyes and titaniumdioxide. Preferred ranges include from about 0.5% to about 25%.

The compositions may be in the form of a sterile injectable solutions oraqueous or oleagenous suspensions. These suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. Cosolvents such as ethanol,propylene glycol or polyethylene glycols may also be used.Preservatives, such as phenol or benzyl alcohol, may be used.

In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations can include emulsions,creams, ointments, gels, pastes, powders, shampoos, pour-onformulations, ready-to-use formulations, spot-on solutions andsuspensions. Topical application of an inventive compound or of acomposition including at least one inventive compound among activeagent(s) therein, a spot-on composition, can allow for the inventivecompound to be distributed through the glands (e.g. sebaceous glands) ofthe animal and/or allow active agent(s) to achieve a systemic effect(plasma concentration) or throughout the haircoat. When the compound isdistributed throughout glands, the glands can act as a reservoir,whereby there can be a long-lasting, e.g. 1-2 months effect or longer.Cotchet and co-workers reported the distribution of fipronil, a1-arylpyrazole compound, to the stratum corneum, the viable epidermisand the sebaceous glands and epithelial layers of beagle dogs afterspot-on administration (see Cochet et al., Eur. J. Drug Metab.Pharmacokinet., 1997, 22(3), 211-216). Using ¹⁴C radiolabeled drug, thepublication demonstrated that fipronil is displaced from the point ofapplication and distributed to the whole skin, where it was persistentlydetected for up to 56 days after treatment. Spot-on formulations aretypically applied in a localized region which refers to an area otherthan the entire animal. In one embodiment of a localized region, thelocation is between the shoulders. In another embodiment, the localizedregion is a stripe, e.g. a stripe from head to tail of the animal.

Pour-on formulations are described, for example, in U.S. Pat. No.6,010,710, which is incorporated herein by reference. The pour-onformulations are advantageously oily, and generally comprise a diluentor vehicle and also a solvent (e.g. an organic solvent) for the activeingredient if the latter is not soluble in the diluent. Pour-onformulation may be administered to livestock animals such as cattle andsheep. In one embodiment, the process comprises applying the solution tolivestock animals before they arrive in the Feed Lot, it being possiblefor this application to be the final one before the animals areslaughtered.

The compositions of the invention can also be formed in a collar such asthose described in U.S. Pat. No. 5,885,607, which is incorporated hereinby reference. Within the scope of the invention, matrices usually usedto make collars may be used. In one embodiment of the collars which maybe mentioned are matrices based on PVC (polyvinyl chloride), asdescribed in U.S. Pat. Nos. 3,318,769; 3,852,416; 4,150,109 and5,437,869, (all incorporated by reference) and other vinyl polymers.

The plasticizers may be chosen in particular from adipates, phthalates,phosphates and citrates. In another embodiment of the collar, one ormore plasticizers are also added to the PVC, these plasticizers beingchosen in particular from the following compounds: diethyl phthalate,dioctyl sebacate, dioctyl adipate, diisodecyl phthalate, acetyl tributylcitrate, diethyl hexyl phthalate, di-n-butyl phthalate, benzyl butylphthalate, acetyl tributyl citrate, tricresyl phosphate, and2-ethylhexyl diphenyl phosphate.

In another embodiment of the collar, a PVC matrix will be used in thepresence of a primary remanent plasticizer and a secondary plasticizer,in particular according to EP 0 539 295 and EP 0 537 998.

Among the secondary plasticizers, mention may be made of the followingproducts: acetyl triethyl citrate, triethyl citrate, triacetin,diethylene glycol monoethyl ether, triphenyl phosphate. A commonstabilizer may also be added thereto.

For the purposes of the present invention, the term external deviceshould be understood to refer to any device which can be attachedexternally to the animal in order to provide the same function as acollar.

In one embodiment of the invention, the active agent is present in theformulation at a concentration of about 0.05 to about 40% (w/v). Inanother embodiment of the invention, the active agent is present in theformulation as a concentration from about 1 to about 30% or about 1 toabout 20% (w/v). In yet another embodiment of the invention, the activeagent is present in the formulation as a concentration from about 5 toabout 15% (w/v). In still another embodiment of the invention, theactive agent is present in the formulation as a concentration about 10%(w/v), about 20% (w/v) or about 30% (w/v).

In one embodiment of the invention, the combination of 1-arylpyrazoleand formamidine is present in the formulation at a concentration ofabout 2% to about 55% (w/v); about 10% to about 35% w/v; or about 18% toabout 27% w/v. In another embodiment of the invention, the amount of1-arylpyrazole is present in the formulation as a concentration of about1% to about 25% (w/v); about 5% to about 15% (w/v); or about 8% to about12% (w/v).

In another embodiment of the invention, the amount of formamidine in theformulations is about 1% to about 30 (w/v); about 5% to about 20% (w/v);or about 10% to about 15% (w/v).

The veterinarily acceptable carrier will generally comprise a diluent orvehicle and also a solvent (e.g. an organic solvent) for the activeingredient if the latter is not soluble, not stable or is degraded inthe diluent.

Organic solvents that can be used in the invention include thosedescribed above, and include but are not limited to: acetyltributylcitrate, oleic acid, fatty acid esters such as the dimethyl ester,diisobutyl adipate, diisopropyl adipate (also known as CERAPHYL 230),ketones including acetone, methylisobutyl ketone (MIK) and methyl ethylketone and the like, acetonitrile, benzyl alcohol, methanol, ethylalcohol, isopropanol, butanol, aromatic ethers such as anisole, butyldiglycol, amides including dimethylacetamide and dimethylformamide,dimethyl sulfoxide, propylene glycol monomethyl ether, propylene glycolmonoethyl ether, dipropylene glycol n-butyl ether, ethylene glycolmonoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide,dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols,propylene glycol, 2-pyrrolidone including N-methylpyrrolidone,diethylene glycol monoethyl ether, ethylene glycol, triacetin, C₁-C₁₀esters of carboxylic acids such as butyl or octyl acetate, benzylacetate, aryl esters including benzyl benzoate, ethyl benzoate and thelike, propylene carbonate, butylene carbonate, and diethyl phthalate, ora mixture of at least two of these solvents.

In one preferred embodiment of the invention, the pharmaceutically orveterinarily acceptable carrier of the formulation comprises C₁-C₁₀alcohols or esters thereof (including acetates, such as ethyl acetateand the like), C₁₀-C₁₈ saturated fatty acids or esters thereof, C₁₀-C₁₈monounsaturated fatty acids or esters thereof, monoesters or diesters ofaliphatic diacids, glycerol monoesters (e.g. monoglycerides), glyceroldiesters (e.g. diglycerides), glycerol triesters (e.g. triglyceridessuch as triacetin), glycols, glycol ethers, glycol esters or glycolcarbonates, polyethylene glycols of various grades (PEGs) or monoethers,diethers, monoesters or diesters thereof (e.g. diethylene glycolmonoethyl ether), or mixtures thereof.

In another embodiment of the invention, the organic solvents maycomprise diisopropyl adipate, dipropylene glycol monomethyl ether,propylene glycol monomethyl ether, 2-pyrrolidone includingN-methylpyrrolidone, diethylene glycol monoethyl ether, triacetin, butylacetate, octyl acetate, propylene carbonate, oleic acid, or a mixture ofat least two of these solvents.

In one embodiment, preferred solvents include C₁-C₁₀ esters ofcarboxylic acids such as butyl or octyl acetate.

Particularly preferred solvents include diethyleneglycol monoethylether, triacetin, butyl acetate and octyl acetate, and mixtures thereof.

In some embodiments, the organic solvent will have a dielectric constantof between about 2 to about 35, between about 10 to about 35, or betweenabout 20 to about 30. In other embodiments, the solvent will have adielectric constant of between about 2 and about 20, or between about 2and about 10. The content of this organic solvent in the overallcomposition will represent the complement to 100% of the composition. Asdiscussed above, the organic solvents with dielectric constants withinthese ranges will typically be aprotic solvents, preferably polaraprotic solvents.

The carrier may comprise a mixture of solvents. In one embodiment, theformulations comprise an organic solvent and an organic co-solvent. Insome embodiments, the formulations comprise a co-solvent having aboiling point of below about 300° C. or below about 250° C. In otherembodiments, the co-solvent has a boiling point of below about 200° C.,or below about 130° C. In other embodiments, the co-solvent has adielectric constant of between about 2 to about 40 or between about 10to about 40. In other embodiments, the co-solvent has a dielectricconstant of between about 20 to about 30. In still another embodiment ofthe invention, the co-solvent has a dielectric constant of between about2 to about 10.

When the formulations comprise an organic solvent and a co-solvent, insome embodiments the co-solvent may be present in the composition in aorganic co-solvent/organic solvent weight/weight (W/W) ratio of betweenabout 1/15 to about 1/2. In some embodiments, the co-solvent is volatileso as to act as a drying promoter, and is miscible with the organicsolvent and may or may not be miscible with water.

The solvent will be used in proportion with the concentration of theactive agent compound and its solubility in this solvent. It will besought to have the lowest possible volume. The vehicle makes up thedifference to 100%.

A vehicle or diluent can be dimethyl sulfoxide (DMSO), glycolderivatives such as, for example, propylene glycol, glycol ethers,polyethylene glycols or glycerol. As vehicle or diluent, mention mayalso be made of plant oils such as, but not limited to soybean oil,groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seedoil, sunflower oil, etc.; mineral oils such as, but not limited to,petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbonsor alternatively, for example, medium-chain (such as C₈ to C₁₂)triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent will be added. One embodiment of the emollientand/or spreading and/or film-forming agents are those agents selectedfrom the group consisting of:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;lecithin, sodium carboxymethylcellulose, silicone oils,polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils),for example those containing silanol functionalities, or a 45V2 oil,

(b) anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulfates (e.g. sodium lauryl sulfate and sodium cetylsulfate); sodium dodecylbenzenesulphonate, sodiumdioctylsulphosuccinate; fatty acids (e.g. those derived from coconutoil),

(c) cationic surfactants such as water-soluble quaternary ammonium saltsof formula N⁺R′R″R′″R″″Y⁻, in which the R radicals are optionallyhydroxylated hydrocarbon radicals and Y⁻ is an anion of a strong acidsuch as the halide, sulfate and sulphonate anions;cetyltrimethylammonium bromide is among the cationic surfactants whichcan be used,

(d) amine salts of formula N⁺R′R″R′″ in which the R radicals areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants which can be used,

(e) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,

(f) amphoteric surfactants such as the substituted lauryl compounds ofbetaine, and

(g) a mixture of at least two of these agents.

In one embodiment of the amount of emollient, the emollient is used in aproportion selected from the group consisting of from about 0.1 to about10%, and about 0.25 to about 5%, by volume.

In another embodiment of the invention, the composition can be inready-to-use solution form as is described, for example, in U.S. Pat.No. 6,395,765, which is incorporated herein by reference. In addition tothe active agent compound, the ready-to-use solution can contain acrystallization inhibitor, an organic solvent and an organic co-solvent.

In some embodiments, the crystallization inhibitor can be present in aproportion of about 1 to about 30% (w/v). Typically, the crystallizationinhibitor may be present in a proportion of about 1% to about 20% (w/v)or about 5% to about 15% (w/v). Acceptable inhibitors are those whoseaddition to the formulation inhibits the formation of crystals when theformulation is applied. In some embodiments, formulations may includecompounds that function as crystallization inhibitors other than thoselisted herein. In these embodiments, the suitability of acrystallization inhibitor may be determined by testing if it willsufficiently inhibit the formation of crystals so that a samplecontaining 10% (w/v) of the 1-arylpyrazole in a solvent as describedabove with 10% (w/v) of the crystallization inhibitor will result inless 20, preferably less than 10 crystals when placed on a glass slideat 20° C. for 24 hours.

Crystallization inhibitors which are useful for the invention includebut are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and of vinylpyrrolidone, 2-pyrrolidone includingN-methylpyrrolidone, dimethylsufoxide, polyethylene glycols, benzylalcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters ofsorbitan; lecithin or sodium carboxymethylcellulose; or acrylicderivatives, such as methacrylates and polymers derived from acrylicmonomers, a solvent as described herein that inhibits thecrystallization of the active agent, and others;

(b) anionic surfactants, such as alkaline stearates (e.g. sodium,potassium or ammonium stearate); calcium stearate or triethanolaminestearate; sodium abietate; alkyl sulfates, which include but are notlimited to sodium lauryl sulfate and sodium cetyl sulfate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids (e.g. coconut oil);

(c) cationic surfactants, such as water-soluble quaternary ammoniumsalts of formula N⁺R′R″R′″R″″Y⁻, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals and Y⁻ is ananion of a strong acid, such as halide, sulfate and sulphonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used;

(d) amine salts of formula N⁺R′R″R′″, in which the R radicals areidentical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used;

(e) non-ionic surfactants, such as optionally polyoxyethylenated estersof sorbitan, e.g. Polysorbate 80, or polyoxyethylenated alkyl ethers;polyethylene glycol stearate, polyoxyethylenated derivatives of castoroil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids or copolymers of ethylene oxide and ofpropylene oxide;

(f) amphoteric surfactants, such as substituted lauryl compounds ofbetaine; or

(g) a mixture of at least two of the compounds listed in (a)-(f) above.

In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents can be selected from the compoundsmentioned above as crystallization inhibitor.

In one embodiment of the film-forming agent, the agents are of thepolymeric type which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants. In anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan. In yet another embodiment of thesurface-active agent, the agents include the various grades ofpolysorbate, for example Polysorbate 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent can be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned above.

The pair thus constituted secures, in a noteworthy way, the objectivesof absence of crystallization on the coat and of maintenance of thecosmetic appearance of the skin or fur, that is to say without atendency towards sticking or towards a sticky appearance, despite thehigh concentration of active material.

The formulation can also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent being present in a proportionselected from a range consisting of about 0.005 to about 1% (w/v), andabout 0.01 to about 0.05% (w/v).

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include, but are not limited to, butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulfate or a mixture of notmore than two of them.

The formulation adjuvants are well known to the practitioner in this artand may be obtained commercially or through known techniques. Theseconcentrated compositions are generally prepared by simple mixing of theconstituents as defined above. Advantageously, the starting point is tomix the active material in the main solvent and then the otheringredients or adjuvants are added.

The volume applied is not restricted as long as the amount of substanceadministered is shown to be safe and efficacious. Typically, the volumeapplied depends on the size and weight of the animal as well as theconcentration of active, the extent of infestation by parasites and thetype of administration. The volume applied is typically of the order ofabout 0.3 to about 1 ml, or about 0.3 ml to about 5 ml, or about 0.3 mlto about 10 ml. In other embodiments, the volume may be about 4 ml toabout 7 ml. For larger animals, the volume may be higher including, butnot limited to, up to 10 ml, up to 20 ml or up to 30 ml, or higher. Inone embodiment of the volume, the volume is on the order of about 0.5 mlto about 1 ml for cats, and on the order of about 0.3 to about 3 ml or 4ml for dogs, depending on the weight of the animal.

In another embodiment of the invention, application of a spot-onformulation according to the present invention can also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

Spot-on formulations are well known techniques for topically deliveringan antiparasitic agent to a limited area of the host. For example, U.S.Pat. Nos. 5,045,536 6,426,333; 6,482,425; 6,962,713; and 6,998,131, allincorporated herein by reference, describe spot-on formulations. WO01/957715, also incorporated herein by reference, describes a method forcontrolling ectoparasites in small rodents as well as interrupting orpreventing the diseases caused by arthropods or small rodents, whichcomprise applying topical formulations, such as spot-on compositions, tothe skin, or hair of the rodents.

For spot-on formulations, the carrier can be a liquid carrier vehicle asdescribed, for example, in U.S. Pat. No. 6,426,333. Liquid carriers forspot-on formulations include the organic solvents and co-solventsdescribed above, among other solvents known in the art.

The liquid carrier vehicle can optionally contain a crystallizationinhibitor such as the crystallization inhibitors described above, ormixtures thereof.

Spot-on formulations, described for example in U.S. Pat. No. 7,262,214(incorporated herein by reference), may be prepared by dissolving theactive ingredients into the pharmaceutically or veterinary acceptablevehicle. Alternatively, the spot-on formulation can be prepared byencapsulation of the active ingredient to leave a residue of thetherapeutic agent on the surface of the animal. These formulations willvary with regard to the weight of the therapeutic agent in thecombination depending on the species of host animal to be treated, theseverity and type of infection and the body weight of the host.

Dosage forms may contain from about 0.5 mg to about 5 g of an activeagent. In one embodiment of the dosage form, the dosage is from about 1mg to about 500 mg of an active agent, typically about 25 mg, about 50mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg, about 800 mg, or about 1000 mg.

Additional veterinary/pharmaceutical active ingredients may be used withthe compositions of the invention. In some embodiments, the additionalactive agents may include, but are not limited to, acaricides,anthelmintics, anti-parasitics and insecticides. Anti-parasitic agentscan include both ectoparasiticidal and endoparasiticidal agents.

Veterinary pharmaceutical agents that may be included in thecompositions of the invention are well-known in the art (see e.g. Plumb′Veterinary Drug Handbook, 5^(th) Edition, ed. Donald C. Plumb, BlackwellPublishing, (2005) or The Merck Veterinary Manual, 9^(th) Edition,(January 2005)) and include but are not limited to acarbose,acepromazine maleate, acetaminophen, acetazolamide, acetazolamidesodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin,acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol,alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproicacid, aminopentamide hydrogen sulfate, aminophylline/theophylline,amiodarone, amitriptyline, amlodipine besylate, ammonium chloride,ammonium molybdenate, amoxicillin, clavulanate potassium, amphotericin Bdesoxycholate, amphotericin B lipid-based, ampicillin, amprolium,antacids (oral), antivenin, apomorphione, apramycin sulfate, ascorbicacid, asparaginase, aspiring, atenolol, atipamezole, atracuriumbesylate, atropine sulfate, aurnofin, aurothioglucose, azaperone,azathioprine, azithromycin, baclofen, barbituates, benazepril,betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate,bleomycin sulfate, boldenone undecylenate, bromides, bromocriptinemesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanoltartrate, cabergoline, calcitonin salmon, calcitrol, calcium salts,captopril, carbenicillin indanyl sodium, carbimazole, carboplatin,carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium,cefixime, chlorsulon, cefoperazone sodium, cefotaxime sodium, cefotetandisodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofursodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins,cephapirin, charcoal (activated), chlorambucil, chloramphenicol,chlordiazepoxide, chlordiazepoxide+/−clidinium bromide, chlorothiazide,chlorpheniramine maleate, chlorpromazine, chlorpropamide,chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine,ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin,clemastine fumarate, clenbuterol, clindamycin, clofazimine,clomipramine, claonazepam, clonidine, cloprostenol sodium, clorazepatedipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine,corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine,cyproheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D,dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate,deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressinacetate, desoxycorticosterone pivalate, detomidine, dexamethasone,dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral),dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazinecitrate, diethylstilbestrol (DES), difloxacin, digoxin,dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol/BAL,dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine,disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate,domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin,doxycycline, edetate calcium disodium.calcium EDTA, edrophoniumchloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin,ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin,epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynicacid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac,etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids(essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim,finasteride, fipronil, florfenicol, fluconazole, flucytosine,fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine,fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxaminemaleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin,gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon,glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine,glyburide, glycerine (oral), glycopyrrolate, gonadorelin, grisseofulvin,guaifenesin, halothane, hemoglobin glutamer-200 (Oxyglobin®), heparin,hetastarch, hyaluronate sodium, hydrazaline, hydrochlorothiazide,hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea,hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate,impenem-cilastatin sodium, imipramine, inaminone lactate, insulin,interferon alfa-2a (human recombinant), iodide (sodium/potassium),ipecac (syrup), ipodate sodium, iron dextran, isoflurane, isoproterenol,isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin,ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose,leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine,lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU),lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine,meclizine, meclofenamic acid, medetomidine, medium chain triglycerides,medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin,meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin,methadone, methazolamide, methenamine mandelate/hippurate, methimazole,methionine, methocarbamol, methohexital sodium, methotrexate,methoxyflurane, methylene blue, methylphenidate, methylprednisolone,metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone,midazolam milbemycin oxime, mineral oil, minocycline, misoprostol,mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone,mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics,neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram,nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine,novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium,omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillinsodium, oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline,oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide,paromomycin sulfate, parozetine, pencillamine, general informationpenicillins, penicillin G, penicillin V potassium, pentazocine,pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline,pergolide mesylate, phenobarbital, phenoxybenzamine, pheylbutazone,phenylephrine, phenypropanolamine, phenyloin sodium, pheromones,parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine,pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril,potassium chloride, pralidoxime chloride, prazosin,prednisolone/prednisone, primidone, procainamide, procarbazine,prochlorperazine, propantheline bromide, propionibacterium acnesinjection, propofol, propranolol, protamine sulfate, pseudoephedrine,psyllium hydrophilic mucilloid, pyridostigmine bromide, pyrilaminemaleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin,s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin,selegiline/1-deprenyl, sertraline, sevelamer, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate,somatotropin, sotalol, spectinomycin, spironolactone, stanozolol,streptokinase, streptozocin, succimer, succinylcholine chloride,sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline, terbutaline sulfate, testosterone,tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopentalsodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium,tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate,tocamide, tolazoline, telfenamic acid, topiramate, tramadol,trimcinolone acetonide, trientine, trilostane, trimepraxine tartratew/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid,vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil,vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarinsodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zincacetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the invention, other arylpyrazole compounds such asphenylpyrazoles described above in the Background, are known in the artand are suitable for combination with the 1-aryl-5-alkyl pyrazolecompounds of the invention. Examples of such arylpyrazole compoundsinclude but are not limited to those described in U.S. Pat. Nos.6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954 and6,998,131 (all of which are incorporated herein by reference, eachassigned to Merial, Ltd., Duluth, Ga.).

In another embodiment of the invention, one or more macrocyclic lactonesor lactams, which act as an acaricide, anthelmintic agent and/orinsecticide, can be added to the compositions of the invention.

The macrocyclic lactones include, but are not limited to, avermectins,such as abamectin, dimadectin, doramectin, emamectin, eprinomectin,ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554 andmilbemycins, such as milbemectin, milbemycin D, moxidectin andnemadectin. Also included are the 5-oxo and 5-oxime derivatives of saidavermectins and milbemycins. Examples of combinations of arylpyrazolecompounds with macrocyclic lactones include but are not limited to thosedescribed in U.S. Pat. Nos. 6,426,333; 6,482,425; 6,962,713 and6,998,131 (all incorporated herein by reference—each assigned to Merial,Ltd., Duluth, Ga.).

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag, or Albers-Schönberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alia, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054.

Macrocyclic lactones are either natural products or are semi-syntheticderivatives thereof. The structure of the avermectins and milbemycinsare closely related, e.g., by sharing a complex 16-membered macrocycliclactone ring. The natural product avermectins are disclosed in U.S. Pat.No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosedin U.S. Pat. No. 4,199,569. Mention is also made of U.S. Pat. Nos.4,468,390, 5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390336, EP 0 002 916, and New Zealand Patent No. 237 086, inter alia.Naturally occurring milbemycins are described in U.S. Pat. No. 3,950,360as well as in the various references cited in “The Merck Index” 12^(th)ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, N.J.(1996). Latidectin is described in the “International NonproprietaryNames for Pharmaceutical Substances (INN)”, WHO Drug Information, vol.17, no. 4, pp. 263-286, (2003). Semisynthetic derivatives of theseclasses of compounds are well known in the art and are described, forexample, in U.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317,4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596,4,973,711, 4,978,677, 4,920,148 and EP 0 667 054.

In another embodiment of the invention, the class of acaricides orinsecticides known as insect growth regulators (IGRs) can also be addedto the compositions of the invention. Compounds belonging to this groupare well known to the practitioner and represent a wide range ofdifferent chemical classes. These compounds all act by interfering withthe development or growth of the insect pests. Insect growth regulatorsare described, for example, in U.S. Pat. Nos. 3,748,356, 3,818,047,4,225,598, 4,798,837, 4,751,225, EP 0 179 022 or U.K. 2 140 010 as wellas U.S. Pat. Nos. 6,096,329 and 6,685,954 (all incorporated herein byreference). Examples of IGRs suitable for use include but are notlimited to methoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron,lufenuron, novaluron, pyrethroids, formamidines such as amitraz,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, andnovaluron.

In yet another embodiment of the invention, adulticide insecticides andacaricides can also be added to the composition of the invention. Theseinclude pyrethrins (which include cinerin I, cinerin II, jasmolin I,jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof) andpyrethroids, and carbamates (which include but are not limited tobenomyl, carbanolate, carbaryl, carbofuran, meththiocarb, metolcarb,promacyl, propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxime andthiofanox).

In some embodiments, the compositions of the invention may include oneor more antinematodal agents including, but not limited to, activeagents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines,organophosphates class of compounds. In some embodiments, benzimidazolesincluding, but not limited to, thiabendazole, cambendazole,parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole,oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and itso,o-dimethyl analogue may be included in the compositions.

In other embodiments, the compositions may include an imidazothiazolecompounds including, but not limited to, tetramisole, levamisole andbutamisole. In still other embodiments, the compositions of theinvention may include tetrahydropyrimidine active agents including, butnot limited to, pyrantel, oxantel, and morantel. Suitableorganophosphate active agents include, but are not limited to,coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos,mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

In other embodiments, the compositions may include the antinematodalcompounds phenothiazine, piperazine as the neutral compound and invarious salt forms, diethylcarbamazine, phenols such as disophenol,arsenicals such as arsenamide, ethanolamines such as bephenium, theniumclosylate, and methyridine; cyanine dyes including pyrvinium chloride,pyrvinium pamoate and dithiazanine iodide; isothiocyanates includingbitoscanate, suramin sodium, phthalofyne, and various natural productsincluding, but not limited to, hygromycin B, α-santonin and kainic acid.

In other embodiments, the compositions of the invention may includeantitrematodal agents. Suitable antitrematodal agents include, but arenot limited to, the miracils such as miracil D and mirasan;praziquantel, clonazepam and its 3-methyl derivative, oltipraz,lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil,various bisphenol compounds known in the art including hexachlorophene,bithionol, bithionol sulfoxide and menichlopholan; varioussalicylanilide compounds including tribromsalan, oxyclozanide,clioxanide, rafoxanide, brotianide, bromoxanide and closantel;triclabendazole, diamfenetide, clorsulon, hetolin and emetine.

Anticestodal compounds may also be advantageously used in thecompositions of the invention including, but not limited to, arecolinein various salt forms, bunamidine, niclosamide, nitroscanate,paromomycin and paromomycin II.

In yet other embodiments, the compositions of the invention may includeother active agents that are effective against artropod parasites.Suitable active agents include, but are not limited to, bromocyclen,chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos,bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos,crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate,dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate,iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos,ronnel, stirofos, allethrin, cyhalothrin, cypermethrin, deltamethrin,fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins,resmethrin, benzyl benzoate, carbon disulfide, crotamiton,diflubenzuron, diphenylamine, disulfuram, isobornyl thiocyanato acetate,methroprene, monosulfuram, pirenonylbutoxide, rotenone, triphenyltinacetate, triphenyltin hydroxide, deet, dimethyl phthalate, and thecompounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde(MGK-11),2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione(MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and2-(octylthio)ethanol (MGK-874).

An antiparasitic agent that can be combined with the compound of theinvention to form a composition can be a biologically active peptide orprotein including, but not limited to, depsipeptides, which act at theneuromuscular junction by stimulating presynaptic receptors belonging tothe secretin receptor family resulting in the paralysis and death ofparasites. In one embodiment of the depsipeptide, the depsipeptide isemodepside (see Willson et al., Parasitology, January 2003, 126(Pt1):79-86).

An insecticidal agent that can be combined with the compound of theinvention to form a composition can be a substituted pyridylmethylderivative compound such as imidacloprid. Agents of this class aredescribed above, and for example, in U.S. Pat. No. 4,742,060 or in EP 0892 060. It would be well within the skill level of the practitioner todecide which individual compound can be used in the inventiveformulation to treat a particular infection of an insect.

In certain embodiments, an insecticidal agent that can be combined withthe compositions of the invention is a semicarbazone, such asmetaflumizone.

In another embodiment, the compositions of the invention mayadvantageously include one or more compounds of the isoxazoline class ofcompounds. These active agents are described in WO 2007/079162, WO2007/075459 and US 2009/0133319, WO 2007/070606 and US 2009/0143410, WO2009/003075, WO 2009/002809, WO 2009/024541, WO 2005/085216 and US2007/0066617 and WO 2008/122375, all of which are incorporated herein byreference in their entirety.

In another embodiment of the invention, nodulisporic acid and itsderivatives (a class of known acaricidal, anthelminitic, anti-parasiticand insecticidal agents) may be added to the compositions of theinvention. These compounds are used to treat or prevent infections inhumans and animals and are described, for example, in U.S. Pat. Nos.5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are herebyincorporated by reference in their entirety. The compositions mayinclude one or more of the known nodulisporic acid derivatives in theart, including all stereoisomers, such as those described in theliterature cited above.

In another embodiment, anthelmintic compounds of the amino acetonitrileclass (AAD) of compounds such as monepantel (ZOLVIX) and the like may beadded to the compositions of the invention. These compounds aredescribed, for example, in WO 2004/024704; Sager et al., VeterinaryParasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13Mar. 2008, 176-181. The compositions of the invention may also includearyloazol-2-yl cyanoethylamino compounds such as those described in US2008/0312272 to Soll et al., which is incorporated herein in itsentirety, and thioamide derivatives of these compounds, as described inU.S. patent application Ser. No. 12/582,486, filed Oct. 20, 2009, whichis incorporated herein by reference.

The compositions of the invention may also be combined withparaherquamide compounds and derivatives of these compounds, includingderquantel (see Ostlind et al., Research in Veterinary Science, 1990,48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997,11, 407-408). The paraherquamide family of compounds are known class ofcompounds that include a spirodioxepino indole core with activityagainst certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics1990, 43, 1380, and J. Antibiotics 1991, 44, 492). In addition, thestructurally related marcfortine family of compounds, such asmarcfortines A-C, are also known and may be combined with theformulations of the invention (see J. Chem. Soc.—Chem. Comm. 1980, 601and Tet. Lett. 1981, 22, 1977). Further references to the paraherquamidederivatives can be found, for example, in WO 91/09961, WO 92/22555, WO97/03988, WO 01/076370, WO 09/004,432, U.S. Pat. No. 5,703,078 and U.S.Pat. No. 5,750,695, all of which are hereby incorporated by reference intheir entirety.

In general, the additional active agent is included in a dose of betweenabout 0.1 μg and about 1000 mg. More typically, the additional activeagent may be included in a dose of about 10 μg to about 500 mg, about 1mg to about 300 mg, about 10 mg to about 200 mg or about 10 mg to about100 mg. In one embodiment of the invention, the additional active agentis included in a dose of between about 1 μg and about 10 mg. In otherembodiments of the invention, the additional active agent may beincluded in a dose of about 5 μg/kg to about 50 mg/kg per weight of theanimal. In other embodiments, the additional active agent may be presentin a dose of about 0.01 mg/kg to about 30 mg/kg, about 0.1 mg/kg toabout 20 mg/kg, or about 0.1 mg/kg to about 10 mg/kg of weight ofanimal. In other embodiments, the additional active agent may be presentin a dose of about 5 μg/kg to about 200 μg/kg or about 0.1 mg/kg toabout 1 mg/kg of weight of animal. In still another embodiment of theinvention, the additional active agent is included in a dose betweenabout 0.5 mg/kg to about 50 mg/kg.

The proportions, by weight, of the combinations of N-aryl-pyrazolecompound/formamidine compound and the additional active agent are forexample between about 1/10,000 and about 10,000/1. More typically, theproportions are in a proportion by weight of about 1/100 to about10,000/1, about 1/1 to about 10,00/1, or about 5/1 to about 10,000/1, orabout preferably about 5/1 to about 1000/1. However, one of ordinaryskill in the art would be able to select the appropriate ratio ofN-aryl-pyrazole compound/formamidine compound and the additional activeagent for the intended host and use thereof.

Optionally, a fragrance may be added to any of the compositions of theinvention. Fragrances which are useful for the invention include but arenot limited to:

(i) carboxylic acid esters such as octyl acetate, isoamyl acetate,isopropyl acetate and isobutyl acetate;

(ii) fragrant oils such as lavender oil.

The compositions of the invention are made by mixing the appropriateamount of N-aryl-pyrazole compound and formamidine compound,veterinarily acceptable solvent and optionally a crystallizationinhibitor, film former, odor dissipation enhancer, etc., to form acomposition of the invention. Various forms (e.g. tablets, pastes,pour-on, spot-on, collars, etc.) of the composition can be obtained byfollowing the method of making these forms described above by thedescription of making these forms found in general formulation textknown to those in the art, e.g. Remington—The Science and Practice ofPharmacy (21^(st) Edition) (2005), Goodman & Gilman's ThePharmacological Basis of Therapeutics (11^(th) Edition) (2005) andAnsel's Pharmaceutical Dosage Forms and Drug Delivery Systems (8^(th)Edition), edited by Allen et al., Lippincott Williams & Wilkins, (2005).

The inventive formulations may contain other inert ingredients such asantioxidants, preservatives, or pH stabilizers. These compounds are wellknown in the formulation art. Antioxidant such as an alpha tocopherol,ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid, sodiumascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylatedhydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol andthe like, may be added to the present formulation. The antioxidants aregenerally added to the formulation in amounts of from about 0.01 toabout 2.0%, based upon total weight of the formulation, with about 0.05to about 1.0% being especially preferred. Preservatives, such as theparabens (methylparaben and/or propylparaben), are suitably used in theformulation in amounts ranging from about 0.01 to about 2.0%, with about0.05 to about 1.0% being especially preferred. Other preservativesinclude benzalkonium chloride, benzethonium chloride, benzoic acid,benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine,chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea,methylparaben, phenol, phenoxyethanol, phenylethyl alcohol,phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate,potassium sorbate, sodium benzoate, sodium propionate, sorbic acid,thimerosal, and the like. Preferred ranges for these compounds includefrom about 0.01 to about 5%.

Compounds which stabilize the pH of the formulation are alsocontemplated. Again, such compounds are well known to a practitioner inthe art as well as how to use these compounds. Buffering systemsinclude, for example, systems selected from the group consisting ofacetic acid/acetate, malic acid/malate, citric acid/citrate, tataricacid/tartrate, lactic acid/lactate, phosphoric acid/phosphate,glycine/glycimate, tris, glutamic acid/glutamates and sodium carbonate.

The compositions of the invention are administered inanti-parasiticidally effective amounts which are determined by the routeof administration, e.g. oral, parenteral, topical, etc. In oneembodiment of the invention, the compositions of the invention areapplied as a pour-on or spot-on formulation.

In each aspect of the invention, the compounds and compositions of theinvention can be applied against a single pest or combinations thereof.

The compositions of the invention that contain 1-arylpyrazole compounds,optionally in combination with a formamidine compound, may beadministered continuously, for treatment or prevention, by knownmethods. In this manner, an effective amount of the compounds isadministered to the animal in need thereof. By “effective amount” isintended a sufficient amount of a composition of the invention toeradicate or reduce the number of parasites infesting the animal.Generally, a dose of from about 0.001 to about 100 mg per kg of bodyweight given as a single dose or in divided doses for a period of from 1to 5 days will be satisfactory but, of course, there can be instanceswhere higher or lower dosage ranges are indicated, and such are withinthe scope of this invention. It is well within the routine skill of thepractitioner to determine a particular dosing regimen for a specifichost and parasite.

In one treatment embodiment, the treatment is carried out so as toadminister to the animal, on a single occasion, a dose containingbetween about 0.001 and about 100 mg/kg of a 1-arylpyrazole compound. Inanother treatment embodiment, the treatment is via a direct topicaladministration such as a pour-on, ready-to-use, spot-on, spray, etc.type formulation. Higher amounts may be provided for very prolongedrelease in or on the body of the animal. In another treatmentembodiment, the amount of 1-arylpyrazole compound for birds and otheranimals which are small in size is greater than about 0.01 mg/kg, and inanother embodiment for the treatment of small-sized birds and otheranimals, the amount of 1-aryl-5-alkyl pyrazole compound is between about1 and about 100 mg/kg of weight of animal.

The solutions according to the invention may be applied using any meansknown per se, e.g. using an applicator gun or a metering flask.

For the pour-on form of the composition, the volume applied can be ofthe order of about 0.3 to about 100 mL. In other embodiments, volumeapplied of the pour-on formulations may be about 1 ml to about 100 ml orabout 1 ml to about 50 ml. In still other embodiments, the volume may beabout 5 ml to about 50 ml or about 10 ml to about 100 ml.

In another embodiment of the invention, application of a spot-onformulation according to the present invention can also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

In another embodiment, application of the two active agents, anN-aryl-pyrazole compound and a formamidine compound can be administeredtogether from separate compartments of a dual-cavity container. In yetanother embodiment, an N-aryl-pyrazole compound and a formamidinecompound can be combined in the same solvent system.

The application of an N-aryl-pyrazole compound and a formamidinecompound would be expected to have efficacy against a wide range ofparasites including fleas, ticks and mites. It was surprising that theapplication of a 1-arylpyrazole compound and a formamidine compound,whether applied from the same solvent system or from different solventsystems, resulted in synergistic effects with respect to efficacyagainst fleas and ticks. It was also surprising that a 1-arylpyrazolecompound and a formamidine compound could be combined, since it has beenobserved that formamidine compounds may degrade in the presence of1-arylpyrazole compounds.

In one embodiment of the method of use, a composition comprising a1-arylpyrazole compound and a formamidine compound has an efficacyagainst ticks of about 80.0% or higher for at least about 37 days. Inanother embodiment of this method of use, a composition comprising a1-arylpyrazole compound and a formamidine compound has an efficacyagainst ticks of about 90.0% or higher for at least about 37 days. Inyet another embodiment of the invention, a composition comprising a1-arylpyrazole compound and a formamidine compound has an efficacy ofabout 95% or higher for about 37 days or longer, about 44 days orlonger, about 51 days or longer or for about 58 days or longer. In stillanother embodiment of the invention, a composition comprising a1-arylpyrazole compound and a formamidine compound has an efficacy ofabout 99% or higher for about 51 days or longer or for about 58 days orlonger. In each of these embodiments of use against ticks, a furtherembodiment of the invention is where the 1-arylpyrazole compound isfipronil; the formamidine compound is amitraz. In another embodiment,the 1-arylpyrazole compound is a 5-alkyl substituted 1-arylpyrazolecompound and the formamidine compound is amitraz.

In another embodiment of the method of use, a composition comprising a1-arylpyrazole compound and a formamidine compound has an efficacyagainst fleas of about 98.5% or higher for about 37 days or longer. Inanother embodiment of this method of use, a composition comprising a1-arylpyrazole compound and a formamidine compound has an efficacyagainst ticks of about 98.5% or higher for about 37 days or longer orabout 44 days or longer. In still another embodiment of this method ofuse, a composition comprising a 1-aryl-pyrazole compound and aformamidine compound has an efficacy against ticks of about 95.0% orhigher for about 51 days or longer. In yet another embodiment, acomposition comprising a 1-arylpyrazole compound and a formamidinecompound has an efficacy of about 99% or higher for about 58 days orlonger. In each of these embodiments of use against ticks, a furtherembodiment of the invention is where the 1-arylpyrazole compound isfipronil; the formamidine compound is amitraz. In another embodiment,the 1-arylpyrazole compound is a 5-alkyl substituted 1-arylpyrazolecompound and the formamidine compound is amitraz.

The synergistic and long-lasting effects of the compositions of theembodiments either applied from the same solvent system or applied fromdifferent solvent systems for each 1-arylpyrazole and for a formamidinemake them suitable for once a month (30 days or a calendar month) oronce very two months (60 days or two calendar months) application of thecomposition in its deliverable form.

The animals that can be treated with the compositions of the inventioninclude but are not limited to birds and mammals (either wild ordomesticated), e.g., livestock and companion animals such as cats, dogs,horses, chickens, sheep, goats, pigs, turkeys and cattle. In oneembodiment of the invention, the mammal is a cat or a dog.

In one embodiment of the location of administration, a singleformulation containing the active agent in a substantially liquidcarrier and in a form which makes possible a single application, or anapplication repeated a small number of times, will be administered tothe animal over a localized region of the animal, e.g. between the twoshoulders. In one embodiment of the invention, the localized region hasa surface area of about 10 cm² or larger. In another embodiment of theinvention, the localized region has a surface are of between about 5 andabout 10 cm² area.

EXAMPLES

The invention is further described by the following non-limitingexamples which further illustrate the invention, and are not intended,nor should they be interpreted to, limit the scope of the invention.

Example 1 Stability of 1-Arylpyrazole Formulations

Compound 1(3-cyano-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-dichlorofluoromethylsulfinyl-5-methyl-1H-pyrazole)was dissolved in a solvent or a combination of two or more solvents at10% w/w. The formulations thus prepared were analyzed, using HPLC, forthe content of compound 1 as the initial timepoint reading. Then allformulations were placed at 50° C., and the content of compound 1 ineach of them was analyzed at the timepoints of two, four, six and, insome cases, 10 weeks. Compound 1 showed good stability in the solventsor combinations of solvents in Table 1 below. Thus formulations ofCompound 1 in the solvents/carriers identified below are shown to besufficiently stable.

TABLE 1 Stability of Formulations of comprising Compound 1 StabilityEvaluation of Formulations (Accelerated @ 50° C.) Compound 1 (%, w/w) 10Form. # Carrier Description Initial 2 wks 4 wks 6 wks wks AN-methylpyrrolidone 8.80 8.78 8.72 9.19 8.80 B butyl acetate/octylacetate 10.41 10.51 10.42 10.32 10.41 C N-methylpyrrolidone/oleic 8.708.95 8.83 9.26 9.25 acid D diethylene glycol 9.10 9.10 8.93 8.99 9.20monoethyl ether/ N-methylpyrrolidone E dipropylene glycol methyl 9.659.60 9.62 9.58 9.62 ether/butyl acetate F diisopropyl adipate 9.36 9.559.44 9.63 9.71 G butyl acetate/octyl acetate/ 10.54 10.58 10.41 10.3210.32 oleic acid H propylene carbonate 8.20 8.30 8.50 8.36 I diethyleneglycol 9.88 9.95 10.06 9.95 monoethyl ether J dipropylene glycol methyl10.45 10.57 10.54 10.81 ether K triacetin 8.49 8.68 8.93 8.90

Example 2 Flea and Tick Efficacy of 1-Arylpyrazole Formulations in Dogs:Study A

An initial clinical study was conducted to test the efficacy of Compound1(3-cyano-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-dichlorofluoromethylsulfinyl-5-methyl-1H-pyrazole)against ticks and fleas in various test formulations. Five test groupsand an untreated control were evaluated. Each test group included sixdogs. Compound was dissolved in a solvent or a combination of two ormore solvents at 10% w/w. Test articles were formulated as topicalspot-on solutions containing compound 1, 10% w/v in a solvent or acombination of solvents as described above. Dogs were infested withapproximately 50 ticks (Rhipicephalus sanguineus) on days −1, 7, 14, 21,28, 35 and 42. Dogs were also infested with approximately 100 fleas(Ctenocephalides felis) on days −1, 8, 15, 22, 29, 36, and 43. Treatmentwas applied by parting the hair and applying the formulation directlyonto the skin on one spot at the midline of the neck, between the baseof the skull and the shoulder blades. The dose rate of each of thetopical solutions was 0.1 ml/kg (10 mg/kg) body weight. The efficacy ofcompound 1 in various formulations is shown Table 2 below. Duration offlea and tick efficacy is shown in Tables 3 and 4 below. As can be seenfrom the tables below, formulations comprising Compound 1 in triacetinformulations provide improved efficacy against fleas and ticks in thisstudy.

TABLE 2 Flea and Tick Efficacy of Compound 1 in Various Formulations.Efficacy Efficacy Efficacy against against against Trt. Dose fleas onfleas on ticks on Group Drug Vol./mg/kg Solvent(s) day 30 (%) day 44 (%)day 44 (%) 1 Untreated NA Commercial FRONTLINE vehicle 2 Compound 1 0.1ml/kg Butyl acetate/octyl 94.5 46.9 −8.6 (10 mg/kg) acetate 3 Compound 10.1 ml/kg Diethylene glycol 91.4 38.9 −10.8 (10 mg/kg) monoethyl ether(transcutol)/N- methyl-2-pyrrolidone 4 Compound 1 0.1 ml/kg Dipropyleneglycol 83.2 31.1 −29.9 (10 mg/kg) monomethyl ether/butyl acetate 5Compound 1 0.1 ml/kg Diisopropyl adipate 92.9 40.3 0.3 (10 mg/kg) 6Compound 1 0.1 ml/kg Triacetin 99.7 93.0 47.8 (10 mg/kg)

TABLE 3 Duration of Flea Efficacy of Compound 1 in Various Formulations.(% efficacy against fleas measured 24 hours after each weeklyinfestation) % Efficacy at Days after Treatment Trt. Day Day Group 2 9Day 16 Day 23 Day 30 Day 37 Day 44 1 0 0 0 0 0 0 0 (control) 2 99.6 100100 99.4 94.5 80.4 46.9 3 96.0 100 99.8 98.8 91.4 85.3 38.9 4 100 100100 99.5 83.2 76.5 31.1 5 100 100 100 100 92.9 69.1 40.3 6 98.0 100 100100 99.7 98.9 93.0

Treatment groups in Table 3 were treated with the drug, dosage andsolvent formulations as indicated in Table 2.

TABLE 4 Duration of Tick Efficacy of Compound 1 in Various Formulations.(% efficacy against ticks measured 24 hours after each weeklyinfestation) % Efficacy at Days after Treatment Treatment Day Day GroupDay 1 Day 2 Day 9 Day 16 Day 23 30 44 1 (control) 0 0 0 0 0 0 0 2 48.667.6 88.1 88.7 41.1 64.0 −8.6 3 59.0 60.8 78.1 81.4 52.2 45.9 −10.8 471.5 72.0 71.2 90.5 38.4 71.7 −29.9 5 71.5 86.0 90.4 83.2 20.4 78.2 0.36 80.7 79.2 83.1 91.7 89.1 72.3 47.8

Treatment groups in Table 4 were treated with the drug, dosage andsolvent formulations as indicated in Table 2. Negative values indicate %increase in tick counts relative to control.

Example 3 Flea and Tick Efficacy of 1-Arylpyrazole Formulations in Dogs:Study B

A separate clinical efficacy study in dogs was designed with anuntreated control group and 5 test groups treated with compound 1. Eachgroup had six dogs. Test articles were formulated as topical spot-onsolutions containing compound 1, 10-20% w/v in a solvent or acombination of solvents as described above. Dogs were infested withapproximately 50 ticks (Rhipicephalus sanguineus) on days −1, 7, 14, 21,28, 35 and 42. Dogs were also infested with approximately 100 fleas(Ctenocephalides felis) on days −1, 8, 15, 22, 29, 36, and 43. Treatmentwas applied by parting the hair and applying the formulation directlyonto the skin on one spot at the midline of the neck, between the baseof the skull and the shoulder blades. The dose rate of each of thetopical solutions was 0.1 ml/kg (10 mg/kg) body weight except fortreatment group 4, which received 0.2 ml/kg (20 mg/kg). The efficacy ofcompound 1 is shown in Table 5 below. Duration of flea and tick efficacyis shown in Tables 6 and 7 below. As can be seen from the table,transcutol renders compound 1 superior efficacy. It should be noted thatStudy A and Study B were conducted at different times and locations, andthe results of each clinical study may differ from the other based onvarious environmental factors. Thus, the results of one clinical studyshould not be compared with those of another due to these factors.

TABLE 5 Flea and Tick Efficacy of Compound 1 in Various Formulations.Efficacy Efficacy against fleas against ticks Trt. on day 58 on day 58Group Drug Dose Solvent(s) (%) (%) 1 Untreated NA Commercial FRONTLINEvehicle 2 Compound 1 0.1 ml/kg Triacetin 99.6 74.6 (10 mg/kg) 3 Compound1 0.2 ml/kg Triacetin 99.0 97.6 (20 mg/kg) 4 Compound 1 0.1 ml/kgDiisopropyl adipate 96.7 89.5 (10 mg/kg) 5 Compound 1 0.1 ml/kgDiethylene glycol monoethyl 100 94.1 (10 mg/kg) ether (transcutol) 6Compound 1 0.1 ml/kg Triacetin/diisopropyl adipate 98.8 88.1 (10 mg/kg)

TABLE 6 Duration of Flea Efficacy of Compound 1 in Various Formulations.(% efficacy against fleas measured 24 hours after each weeklyinfestation) % Efficacy at Days after Treatment Trt Day Day Day Day DayDay Day Day Day Group 2 9 16 23 30 37 44 51 58 1 (con- trol) 2 100 100100 99.8 99.7 99.8 100 99.8 99.6 3 100 100 100 99.8 100 100 100 99.799.0 4 100 100 100 100 100 98.9 99.6 98.5 96.7 5 100 100 100 99.8 100100 100 100 100 6 100 100 100 99.8 100 100 100 100 98.8

Treatment groups in Table 6 were treated with the drug, dosage andsolvent formulations as indicated in Table 5.

TABLE 7 Duration of Tick Efficacy of Compound 1 in Various Formulations.(% efficacy against ticks measured 24 hours after each weeklyinfestation) % Efficacy at Days after Treatment Trt Day Day Day Day DayDay Day Day Day Group 1 2 9 16 23 30 44 51 58 1 (con- trol) 2 94.8 99.6100 100 100 98.8 94.5 90.8 74.6 3 93.9 98.9 100 100 100 100 99.4 99.397.6 4 95.6 98.9 100 100 99.1 99.1 93.4 87.9 89.5 5 87.4 98.5 100 100100 98.8 98.5 98.9 94.1 6 94.8 99.6 100 100 100 98.8 96.6 91.6 88.1

Treatment groups in Table 7 were treated with the drug, dosage andsolvent formulations as indicated in Table 5.

Example 4 Flea and Tick Efficacy of 1-Arylpyrazole Formulations in Dogs:Study C

The effectiveness of Compound 1 alone, fipronil alone, Compound 1 incombination with amitraz, or fipronil in combination with amitraz, whenadministered once as topical solutions to dogs against inducedinfestations of Rhipicephalus sanguineus and Ctenocephalides felis weredetermined in a third clinical study. Thirty-six beagles (18 males and18 females) were selected for the study. Six replicates of 6 animalseach were formed. Treatment Group 1 dogs were treated with a placebo.Treatment Groups 2, 3, 4, 5 and 6 received their respective treatmentsas a topical spot-on application once on Day 0. Each formulationincluded diethyleneglycol monoethyl ether (transcutol) as carrier. TheTreatment Groups were: Treatment Group 2: fipronil at 0.1 mL/kg bodyweight (10 mg/kg); Treatment Group 3: Compound 1 at 0.1 mL/kg (10 mg/kg)body weight; Treatment Group 4: Compound 1 at 0.2 mL/kg (20 mg/kg) bodyweight; Treatment Group 5: Compound 1 at 0.1 mL/kg (10 mg/kg) bodyweight plus amitraz at 0.04 mL/kg (8 mg/kg) body weight; Treatment Group6: fipronil at 0.1 mL/kg (10 mg/kg) body weight plus amitraz at 0.04mL/kg (8 mg/kg) body weight. Treatment was applied by parting the hairand applying the formulation(s) directly onto the skin on one spot atthe midline of the neck, except for Groups 4, 5 and 6 which were appliedin approximately equal volumes on two spots, one spot between the baseof the skull and the shoulder blades and the other at the front of theshoulder blades.

All dogs were infested with approximately 50 Rhipicephalus sanguineusticks on Days −1, 7, 14, 21, 28, 35, 42, 49 and 56. Dogs were alsoinfested with approximately 100 Ctenocephalides felis fleas on Days −1,8, 15, 22, 29, 36, 43, 50 and 57. Ectoparasites were removed and countedon Day 2, approximately 48 hours after treatment and on Days 9, 16, 23,30, 37, 44, 51 and 58 approximately 24 hours after flea infestation and48 hours after tick infestation. Tables 8 and 9 below show the %efficacy of formulations comprising fipronil at 0.1 ml/kg of bodyweight, Compound 1 at 10 ml/kg and 20 ml/kg, and fipronil and Compound 1both at 10 ml/kg in combination with amitraz at 0.04 ml/kg of bodyweight compared to control group without active compounds. The percentreduction in flea counts of the treated groups with respect to theControl group over the study is shown in Figure 14.

TABLE 8 Duration of Flea Efficacy of Compound 1 and Fipronil Alone andWith Amitraz.(% efficacy against fleas measured 24 hours after eachweekly infestation) % Efficacy at Days after Treatment Trt Day Day DayDay Day Day Day Group DRUG Day 2 Day 9 16 23 30 37 44 51 58 1 (control)2 Fipronil 100 100 100 100 100 100 99.8 100 99.1 10 mg/kg 3 Cmpd 1 100100 100 100 99.8 99.4 98.6 98.5 94.6 10 mg/kg 4 Cmpd 1 100 100 100 100100 100 100 99.8 100 20 mg/kg 5 Cmpd 1, 10 mg/kg + 100 100 100 100 100100 100 100 100 amitraz 8 mg/kg 6 Fipronil 10 mg/kg + 100 100 100 100100 100 100 100 100 amitraz 8 mg/kg

TABLE 9 Duration of Tick Efficacy of Compound 1 and Fipronil Alone andWith Amitraz.(% efficacy against fleas measured 48 hours after eachweekly infestation) % Efficacy at Days after Treatment Trt Day Day DayDay Day Day Day Day Group Day 1 Day 2 Day 8 Day 9 15 16 23 30 37 44 5158 1 (control) 2 88.6 90.9 99.4 100 100 100 98.8 100 99 98.2 92.8 82.7 388.1 96.8 93.5 97.7 98.5 100 98.4 99 94.3 92.4 84.7 83.1 4 98.6 98.998.6 100 99.3 100 100 99.5 98.6 92.3 86.5 87.4 5 90 100 100 100 100 10099.4 100 100 99.6 97 72.9 6 87.9 98.9 100 100 100 100 100 100 100 100100 99.5 Treatment Group 2: fipronil 10 mg/kg; Group 3: Cmpd 1 10 mg/kg;Group 4: Cmpd 1 20 mg/kg; Group 5: Cmpd 1 (10 mg/kg) + amitraz (8mg/kg); Group 6: fipronil (10 mg/kg) + amitraz (8 mg/kg)

Example 5 Flea Efficacy of 1-Arylpyrazole Formulations in Cats: Study D

A fourth clinical study was conducted to determine the efficacy oftopically administered Compound 1 and fipronil against inducedinfections of Ctenocephalides felis in cats. Twenty four cats (17 males,7 females) were included in the study. Six replicates of four cats eachwere formed based on decreasing Day −5 flea counts. Within replicates,cats were randomly allocated to Treatment Groups 1, 2, 3 or 4,respectively, by using a die: Group 1—untreated (vehicle control); Group2—Compound 1 (10 mg/kg); Group 3—Compound 1 (20 mg/kg); Group 4—fipronil(10 mg/kg). Treatment was performed by topical administration of theformulations in the midline of the neck, between the base of the skulland the shoulder blades in a single spot after parting the hair. Animalswere observed hourly for approximately four hours following treatment.

The cats were infested with approximately 100 Ct. felis fleas eachduring acclimation on Day −6 for allocation purposes, and on Days −1,14, 21, 28, 35 and 42 for treatment efficacy evaluation purposes. Thefleas were removed by combing each cat approximately 24 hours followingeach infestation except for the Day −1 infestation which was followed byflea removal and count on Day 1 (˜48 hours following infestation). Table10 below shows the % efficacy of each treatment group compared to thecontrol group.

TABLE 10 Duration of Flea Efficacy of Compound 1 and Fipronil (%efficacy against fleas measured 24 hours after each weekly infestation)Treatment % Efficacy at Days after Treatment Group Day 1 Day 15 Day 22Day 29 Day 36 Day 43 1 (control) 2 99.84 99.81 100 100 99.43 97.28 3 100100 100 100 100 100 4 97.96 100 100 95.59 99.24 97.81 Treatment Group 2:Cmpd 1 10 mg/kg; Group 3: Cmpd 1 20 mg/kg; Group 5: fipronil (10 mg/kg)

Flea counts on Days 1, 15, 22, 29, 36 and 43 indicated >97% efficacyagainst C. felis in Group 2 and 4 animals. Flea counts of Group 3animals indicated 100% efficacy against C. felis at all time points. Thestudy demonstrates the excellent efficacy of Compound 1 both at 10 mg/kgand 20 mg/kg against fleas in cats. Figure

Example 6 Stable Formulations Comprising Amitraz

Several formulations comprising amitraz in different carriers/solventswere prepared according the procedures below to evaluate the stabilityof amitraz in the formulations and to determine whether amitraz wassufficiently soluble in the formulations.

Formulation L

Anisole was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Amitraz was added to the anisolesolution with stirring and the stirring was continued until the amitrazwas fully dissolved. The volume was adjusted to 100% with anisole.

Ingredients Function % Amitraz Active 28.0 w/v Anisole Solvent q.s. 100Formulation M

Butyl acetate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Amitraz was added to the butylacetate solution with stirring and the stirring was continued until theamitraz was fully dissolved. The volume was adjusted to 100% with butylacetate.

Ingredients Function % Amitraz Active 25.0 w/v Butyl acetate Solventq.s. 100Formulation N

Ethyl benzoate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Amitraz was added to the ethylbenzoate solution with stirring and the stirring was continued until theamitraz was fully dissolved. The volume was adjusted to 100% with ethylbenzoate.

Ingredients Function % Amitraz Active 28.0 w/v Ethyl benzoate Solventq.s. 100Formulation O

Benzyl benzoate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Amitraz was added to the benzylbenzoate solution with stirring and the stirring was continued until theamitraz is fully dissolved. The volume was adjusted to 100% with benzylbenzoate.

Ingredients Function % Amitraz Active 25.0 w/v Benzyl benzoate Solventq.s. 100Formulation P

Butyl acetate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Anisole was added to the butylacetate solution and mixed. Amitraz was then added to the anisole/butylacetate solution with stirring and the stirring was continued until theamitraz is fully dissolved. The volume was adjusted to 100% with butylacetate.

Ingredients Function % Amitraz Active 25.0 w/v Anisole Solvent 10.0 v/vButyl acetate Solvent q.s. 100Formulation Q

Butyl acetate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Methyl isobutyl ketone was addedto the butyl acetate solution and mixed. Amitraz was then added to themethyl isobutyl ketone/butyl acetate solution with stirring and thestirring was continued until the amitraz was fully dissolved. The volumewas adjusted to 100% with butyl acetate.

Ingredients Function % Amitraz Active 25.0 w/v Methyl isobutyl ketoneSolvent 10.0 v/v Butyl acetate Solvent q.s. 100Formulation R

Butyl acetate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Benzyl benzoate was added to thebutyl acetate solution and mixed. Amitraz was then added to the benzylbenzoate/butyl acetate solution with stirring and the stirring wascontinued until the amitraz was fully dissolved. The volume was adjustedto 100% with butyl acetate.

Ingredients Function % Amitraz Active 25.0 w/v Benzyl benzoate Solvent 5.0 v/v Butyl acetate Solvent q.s. 100Formulation S

Butyl acetate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Ethyl benzoate was added to thebutyl acetate solution and mixed. Amitraz was then added to the ethylbenzoate/butyl acetate solution with stirring and the stirring wascontinued until the amitraz was fully dissolved. The volume was adjustedto 100% with butyl acetate.

Ingredients Function % Amitraz Active 25.0 w/v Ethyl benzoate Solvent 5.0 v/v Butyl acetate Solvent q.s. 100Formulation T

Butyl acetate was added in the amount of about 50% of the volume to beprepared into a flask with a stopper. Benzyl acetate was added to thebutyl acetate solution and mixed. Amitraz was then added to the benzylacetate/butyl acetate solution with stirring and the stirring wascontinued until the amitraz was fully dissolved. The volume was adjustedto 100% with butyl acetate.

Ingredients Function % Amitraz Active 20.0 w/v Benzyl acetate Solvent10.0 v/v Butyl acetate Solvent q.s. 100

Example 7 Stability of Amitraz in Solution

Formulation comprising amitraz in anisole (formulation L), butyl acetate(formulation M), methyl isobutyl ketone and ethyl benzoate wereevaluated for stability by HPLC, similarly to the stability study forformulations comprising compound 1. Thus the formulations were testedfor initial concentration of amitraz % (w/v) and aged at 50° C. forthree months. The concentration of amitraz in each formulation wasdetermined at 1 month, 2 months and 3 months to determine the stabilityof amitraz in each formulation. As shown in Table 11 below, formulationsof amitraz in anisole, butyl acetate and methyl isobutyl ketone do notshow degradation at these conditions.

TABLE 11 Stability of Amitraz Formulations % Amitraz % theoreticalFormulation Solvent: (w/v) 1 month 2 months 3 months Anisole(formulation L) 28 101 101 97 Butyl acetate (formulation M) 25 104 102105 Methyl isobutyl ketone (MIK) 28 93 98 100 Ethyl benzoate(formulation N) 28 98 96 94

Example 8 Solubility of Amitraz in Solution

The solubility of amitraz in various solvents is shown in Table 12below. Solutions of amitraz in certain solvents at high concentrationresult in the appearance of crystals over time. For example, FormulationP above resulted in a small amounts of crystal formation after 1 week ofstorage [at ambient temperature. However, when the concentration ofamitraz in this formulation was decreased to 20% w/v, no crystalformation was observed after 1 week of storage. Formulation Q showed nocrystallization after 1 week of storage. The solubility of amitraz inbutyl acetate is lower then in anisole, MIK and ethyl benzoate. It hasbeen observed during clinical studies that formulation of amitraz (25%)in butyl acetate produced white crystals on the coat of animals,therefore small amounts of other solvent, with higher solubility ofamitraz, were added. Additionally, when amitraz (25%) in butyl acetateformulations were stored at 50° C. in a chamber, they evaporatedslightly. Upon cooling to room temperature, these solutions precipitatedcrystals. Again, lowering concentration to 20% and addition ofco-solvents with higher solubility of amitraz avoided crystallization ofamitraz. Unexpectedly, this addition of co-solvents caused the effectsdescribed below in Example 9.

TABLE 12 Solubility of Amitraz Solubility of amitraz Dielectric Solvent(at room temperature, %) Constant of solvent Acetone 37.87 20.7 Anisole45.54 4.33 (methoxybenzene) Benzyl benzoate 33.30 4.8 Benzyl acetate21.85 5.0 Butyl acetate 27.10 5.0 Ethyl benzoate 39.43 6.02 Methylisobutyl ketone 36.72 13.1

Example 9 Effect of Solvent on Odor and Odor Dissipation

Amitraz solutions in a single solvent exhibited an unpleasant smell thatlasted from about 30 minutes to about 90 minutes when applied to filterpaper. However, when the solutions of Formulations P and Q were appliedto filter paper, the smell disappeared after only about 10 to about 15minutes.

Example 10 Efficacy of Combination of Fipronil with Amitraz AgainstTicks on Dogs

A fipronil formulation (commercial product) was prepared and storedseparately from amitraz. Amitraz was formulated with the same carrier.Both parts, fipronil and amitraz in solvent(s) were stored separatelyand applied simultaneously. Amounts applied were calculated to keep doseat 10% (w/v) each in final formulation and 10 mg/kg BW of actives inamount applied.

Table 13 below shows the percent efficacy after topical application ofthe formulations comprising amitraz alone, fipronil alone or amitraz andfipronil to dogs. In brief, treatment was applied by parting the hair onthe midline of the neck, between the base of the skull and the shoulderblades, and applying the formulation directly onto the skin.

TABLE 13 Efficacy of Compositions Comprising Amitraz and FipronilAgainst Ticks Days after treatment 2 16 23 30 37 44 Fipronil + 98.8 98.4100 97.7 94.2 79.5 Amitraz Comparative 90.9 100 99.3 53.9 43.9 37.9Fipronil Comparative 95.1 96.9 95.0 64.9 56.2 28.3 Amitraz

As can be seen from the data above, the combination of fipronil andamitraz shows markedly better efficacy against ticks than the use offipronil or amitraz alone. Fipronil and amitraz were found to becompatible with each other when administered simulataneously to theanimals.

Example 11 Efficacy of Combination of Fipronil and Amitraz Against Fleason Dogs

The amitraz and fipronil composition described in Example 10 were usedin this study. Table 14 below shows the percent efficacy after topicalapplication of the formulation to dogs. Treatment was applied by partingthe hair on the midline of the neck, between the base of the skull andthe shoulder blades, and applying the formulation directly onto theskin.

TABLE 14 Efficacy of Compositions Comprising Fipronil and AmitrazAgainst Fleas Days after treatment 2 16 23 30 37 44 51 Fipronil + 99.6100 100 100 100 98.2 95.7 Amitraz Comparative 100 100 100 94.4 63.4 55.974.7 Fipronil Comparative 14.3 12.4 16.3 20.2 32.5 25.9 — Amitraz

As can be seen from the data in Table 14 above, the combination offipronil and amitraz shows markedly better efficacy against fleas thanthe use of fipronil or amitraz alone and is also surprising from thestandpoint that fipronil and amitraz were found to be compatible witheach other.

Example 12 Synergistic Effect of Fipronil with Amitraz in Tick ContactAssay

Fipronil was dissolved in acetone containing 0.019% of a mixture ofTriton 152 and Triton 172 (1:3, v/v) and 0.4% DMSO to achieve thedesired concentration. Dosages were serially diluted using this sameformulation. For treatments containing amitraz, amitraz was added to theabove solution to achieve the desired concentration. 0.5 ml of thesolution was used to treat 20 ml scintillation vials containing a 0.125″hole in the cap. This was achieved by rolling the uncapped vials untilthe acetone had evaporated thus leaving the walls of the vial coatedwith the experimental compound(s). Filter papers treated with this samesolution were placed in the cap and bottom of the treated vial. Vialswere capped and held over night at 24° C. and 95% RH after which 10adult Rhipicephalus sanguineus ticks were placed into each vial. Thevials were held under the same conditions mentioned above for theduration of the test. The number of living and dead ticks in each vialwas determined at 6, 24 and 48 hrs. Tables 15 and 16 below show theefficacy of fipronil alone and fipronil in combination with amitraz atvarious concentrations. Table 17 presents synergistic ratios of amitrazand fipronil and shows the calculated EC50 and EC90 values at 6 hours,24 hours and 48 hours for fipronil alone and the combination of fiproniland amitraz.

TABLE 15 Tick Efficacy of fipronil in DMSO contact Test 6 hour %Mortality 24 hour % Mortality 48 hour % Mortality Rate Avg. % Avg. %Avg. % Cmpd. ppm Rep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality Rep 1 Rep 2Mortality fipronil 25 40 60 50 80 90 85 100 100 100 6.25 0 20 10 90 5070 100 100 100 1.6 0 0 0 20 40 30 50 60 55 0.4 0 0 0 0 0 0 20 20 20 0.10 0 0 0 0 0 0 0 0 0.025 0 0 0 0 0 0 0 0 0 0.006 0 0 0 0 0 0 0 0 0 0.00160 0 0 0 0 0 0 0 0 Solvent 0 0 0 0 0 0 0 0 0 control Untreated 0 0 0 0 00 0 0 0 Control Rate is the ppm of the solution used to treat the vials.

TABLE 16 Synergistic Tick Efficacy of Fipronil with Amitraz in DMSOContact Test 6 hour % Mortality 24 hour % Mortality 48 hour % MortalityRate Avg. % Avg. % Avg. % Cmpd ppm Rep 1 Rep 2 Mortality Rep 1 Rep 2Mortality Rep 1 Rep 2 Mortality fipronil + 25 100 100 100 100 100 100100 100 100 Amitraz 6.25 100 100 100 100 100 100 100 100 100 (12.5 ppm)1.6 30 60 45 100 100 100 100 100 100 0.4 0 10 5 100 100 100 100 100 1000.1 0 0 0 90 80 85 90 80 85 0.025 0 0 0 60 40 50 60 40 50 0.006 0 0 0 2030 25 20 30 25 0.0016 0 0 0 0 0 0 0 0 0 Amitraz 25 0 0 0 0 0 0 10 10 1012.5 0 0 0 0 0 0 0 0 0 6.25 0 0 0 0 0 0 0 0 0 Solvent 0 0 0 0 0 0 0 0 0control Untreated 0 0 0 0 0 0 0 0 0 Control Rate is the ppm of thesolution used to treat the vials.

TABLE 17 EC50, EC90 and Synergistic Ratios of Tick Efficacy of Fipronilwith Amitraz in DMSO Contact Test 6 hour Eval 24 hour Eval 48 hour EvalCompound EC50 EC90 EC50 EC90 EC50 EC90 fipronil 25 >25 3.45 >25 1.245.17 fipronil + 1.7 3.7 0.022 0.16 0.022 0.16 Amitraz (12.5 ppm)Synergistic 14.7 >6.76 156.8 >156 56.4 32.3 Ratio for fipronilSynergistic ratio is EC50 or EC90 alone divided by EC50 or EC90 withAmitraz.

Example 13 Synergistic Effect of Fipronil with Amitraz at DifferentDosages in Tick Contact Assay

Another study shown in Tables 18 and 19 below further demonstrate thesynergistic efficacy of fipronil and amitraz. The assay protocol wassimilar to the protocol of Example 12, with the following exceptions: 1)The vials were visually evaluated at 4, 24 and 48 hours post infestationfor living/dead ticks and percent mortality was determined, and 2) theamitraz was added at dosages of 12.5 ppm, 6.25 ppm, and 3.13 ppm.

TABLE 18 Tick Efficacy of fipronil in DMSO contact Test 4 hour %Mortality 24 hour % Mortality 48 hour % Mortality Rate Avg. % Avg. %Avg. % Compound ppm Rep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality Rep 1Rep 2 Mortality fipronil 25 80 90 85 100 100 100 100 100 100 6.25 10 2015 100 90 95 100 90 95 1.6 0 0 0 70 30 50 100 70 85 0.4 0 0 0 0 0 0 0 00 0.1 0 0 0 0 0 0 0 0 0 0.025 0 0 0 0 0 0 0 0 0 Solvent 0 0 0 0 0 0 0 00 control Untreated 0 0 0 0 0 0 0 0 0 Control Rate is the ppm of thesolution used to treat the vials.

TABLE 19 Synergistic Tick Efficacy of Fipronil with Different Dosages ofAmitraz in DMSO Contact Test 4 hour % Mortality 24 hour % Mortality 48hour % Mortality Rate Avg. % Avg. % Avg. % Compound ppm Rep 1 Rep 2Mortality Rep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality Fipronil + 25 100100 100 100 100 100 100 100 100 Amitraz (12.5 ppm) 6.25 100 100 100 100100 100 100 100 100 1.6 20 30 25 100 100 100 100 100 100 0.4 0 0 0 100100 100 100 100 100 0.1 0 0 0 90 90 90 90 90 90 0.025 0 0 0 50 50 50 5050 50 Fipronil + 25 100 100 100 100 100 100 100 100 100 Amitraz (6.25ppm) 6.25 80 70 75 100 100 100 100 100 100 1.6 10 0 5 100 100 100 100100 100 0.4 0 0 0 100 100 100 100 100 100 0.1 0 0 0 90 90 90 90 100 950.025 0 0 0 60 40 50 60 60 60 Fipronil + 25 100 100 100 100 100 100 100100 100 Amitraz 6.25 40 30 35 100 100 100 100 100 100 (3.13 ppm) 1.6 0 00 100 100 100 100 100 100 0.4 0 0 0 100 100 100 100 100 100 0.1 0 0 0100 100 100 100 100 100 0.025 0 0 0 60 60 60 60 60 60 Amitraz 25 0 0 0 00 0 0 0 0 12.5 0 0 0 0 0 0 0 0 0 6.25 0 0 0 0 0 0 0 0 0 3.13 0 0 0 0 0 00 0 0 Solvent 0 0 0 0 0 0 0 0 0 control Untreated 0 0 0 0 0 0 0 0 0ControlTable 20 below shows the calculated EC50 and EC90 values for this studyfor fipronil alone and three different combinations of fipronil withamitraz. As the table shows, combinations of fipronil with amitraz aresignificantly more potent than fipronil alone even just 4 hours afteradministration.

TABLE 20 EC50, EC90 and Synergistic Ratios of Fipronil with DifferentDosages of Amitraz in Tick Contact Test 4 hour Eval 24 hour Eval 48 hourEval Compound EC50 EC90 EC50 EC90 EC50 EC90 fipronil 12.5 >25 1.61 3.71.19 1.73 fipronil + 1.7 1.91 0.025 0.098 0.025 0.098 Amitraz (12.5 ppm)fipronil + 4.31 9.03 0.025 0.098 <0.025 0.066 Amitraz (6.25 ppm)fipronil + 6.48 7.31 <0.025 0.031 <0.025 0.031 Amitraz (3.13 ppm)Synergistic Ratios fipronil with 7.35 >13 64.4 37.8 47.6 17.7 Amitraz at12.5 ppm fipronil with 2.9 >2.8 64.4 37.8 >47.6 26.2 Amitraz at 6.25 ppmfipronil with 1.9 >3.4 >64.4 119.4 >47.6 55.8 Amitraz at 3.13 ppmSynergistic ratio is EC50 or EC90 alone divided by EC50 or EC90 withAmitraz.

Example 14 Tick Motility of Synergistic Formulations Comprising Amitrazand Fipronil

The synergistic efficacy of combinations of fipronil and amitraz wasdemonstrated by measuring the motility of ticks exposed to anenvironment containing different amounts of fipronil alone, amitrazalone or combinations of fipronil and amitraz. An imaging system wasused for the automated analysis of tick motility in response to amitrazand fipronil treatments to remove the subjective interpretation ofmanual test evaluation. The study was designed to evaluate the affect ofamitraz and fipronil alone and in combination, as compared to a control,on the motility of ticks over time.

The motility of adult Rhipicephalus sanguineus was compared foramitraz-only, fipronil-only and the combination of fipronil and amitrazin a petri dish assay using the imaging system. The assay was run usinga fixed dilution of amitraz (0.32 ug/cm²), with serial dilutions offipronil (1.3, 0.33, 0.08, 0.02, or 0.005 ug/cm²) alone and incombination with the fixed dilution of amitraz. Six independentreplications were conducted.

A plate holding four petri dishes was custom made for the imagingsystem. At each time point the plate holding four petri dishes wasplaced on the imaging system and evaluated for motility. The set up ofthe plate for each evaluation is illustrated below in Table 21.

TABLE 21 Tick Motility Set Up Petri Dish Desig- nation Plate 1 Plate 2Plate 3 Plate 4 Plate 5 A1 Ethanol Ethanol Ethanol Ethanol EthanolControl Control Control Control Control A2 Amitraz Amitraz AmitrazAmitraz Amitraz 0.32 0.32 0.32 0.32 0.32 μg/cm² μg/cm² μg/cm² μg/cm²μg/cm² B1 Fipronil Fipronil Fipronil Fipronil Fipronil 1.3 0.33 0.080.02 0.005 μg/cm² + μg/cm² + μg/cm² + μg/cm² + μg/cm² + Amitraz AmitrazAmitraz Amitraz Amitraz 0.32 0.32 0.32 0.32 0.32 μg/cm² μg/cm² μg/cm²μg/cm² μg/cm² B2 Fipronil Fipronil Fipronil Fipronil Fipronil 1.3 0.330.08 0.02 0.005 μg/cm² μg/cm² μg/cm² μg/cm² μg/cm²

For Dish A1, a volume of 625 μL of ethanol was used to treat the topsand 625 μL to treat the bottoms of the petri dish. All solutions wereformulated in 100% ethanol. For Dish A2, a volume of 125 μL of the 25ppm amitraz solution was used to treat the tops and 125 μL to treat thebottoms of the petri dish. For Dish B1, the top and bottom portions ofthe petri dishes were each treated with 500 μL of the 25 ppm solution offipronil (serially diluted for each Plate 1-5) and 125 μL of the 25 ppmsolution of amitraz. And for Dish B2, each of the top and bottomportions of the petri dishes were treated with 500 μL of the 25 ppmsolution of fipronil (serially diluted for each Plate 1-5). Afterapplication of the corresponding solution to the petri dishes, the petridishes were left open under a fan and allowed to dry for 1 hour. Afterdrying, the dishes were infested with 10 adult Rhipicephalus sanguineus(supplied by Ecto Services, Inc. Henderson, N.C.). The ticks were leftundisturbed for 1 hour before evaluation in the imaging system. Betweenevaluations ticks were maintained at approximately 21° C. and 60% RH.

After the initial hour, each Plate 1-5 was sequentially placed into theimaging system for evaluation. Image processing calculates the change inmovement of the ticks between each image. The value generated is equalto the movement in each petri dish during the image time. The ticks ineach individual petri dish were then stimulated to move bybreathing/exhaling into the plate. After stimulation, the plates wereplaced back into the imaging system for another evaluation to determineif the treatment affected the tick's ability to move. Image capture wasrepeated as in the pre-stimulated evaluation.

Evaluations were made at 1, 4, 18, and 24 hours post infest (hpi) for 3trials. For 3 trials the 4 hour evaluation was not done and for 3 trialsthe third evaluation was done at 21 to 22 hours. Raw data values wereexported from the imaging system and comparative analysis of treatmentsover time was conducted. The geometric means of the movement values forstimulated ticks from all time points are shown in Table 22.

TABLE 22 Geometric Means of movement values for stimulated ticks at alltime points. Hours Post Treatment Geometric Infestation Group Mean 1Control 43,300 1 Amitraz 56,900 1 Fipronil + Amitraz 59,400 1 Fipronil51,000 4 Control 30,600 4 Amitraz 44,300 4 Fipronil + Amitraz 38,500 4Fipronil 29,000 18 Control 30,400 18 Amitraz 33,200 18 Fipronil +Amitraz 3,700 18 Fipronil 17,400 21-22 Control 25,000 21-22 Amitraz30,300 21-22 Fipronil + Amitraz 1,990 21-22 Fipronil 21,200 24 Control27,600 24 Amitraz 34,300 24 Fipronil + Amitraz 598 24 Fipronil 19,700

Typically adult R. sanguineus will rest unless there is a source ofstimulation, such as movement or CO₂. The amitraz-only treated ticks hadan increase in motility as compared to the solvent control treated ticksover time (FIG. 11). Fipronil-only treated ticks showed a reduction inmotility directly correlated to the dose response over time. At 18 and21 hpi the doses as low as 0.08 μg/cm² of fipronil in the fipronil plusamitraz combination show the greatest reduction in motility. The ticksin the fipronil treatment group were not affected in this manner. Forthe 18, 21-22, and 24 hpi, evaluations only the highest dose of fipronil(1.3 μg/cm²) had consistently low motility values after stimulation. Thedifference in the dose response for fipronil and fipronil plus amitrazillustrates that a lower amount of fipronil was adequate in combinationwith amitraz to cause the ticks to become non-motile. This greaterreduction in motility for fipronil plus amitraz was also measured at the24 hpi time point down to the 0.02 μg/cm² dose of fipronil tested. Basedon these results, the combination of fipronil and amitraz led to agreater reduction in motility at the later time points (FIG. 11). Thisresults in a synergistic effect between the fipronil and amitraz.

Example 15 Tick Efficacy of Synergistic Formulations Comprising Amitrazand Compound 1—Tick DMSO Contact Assay

Scintillation vials were treated with commercial and experimentalcompounds using the same procedure described in Example 12 above. Thetreated vials were used to determine the contact toxicity of compoundsagainst adult brown dog ticks (Rhipicephalus sanguineus). The ticks weresupplied by Ecto Services Inc. Henderson, N.C.

Unfed adult ticks were released into a metal pan and 10 living tickswere aspirated into each vial. The vials were visually evaluated at 6,24 and 48 hours post infestation for living/dead ticks and percentmortality was determined. Two replicates were tested for each treatmentand the results were averaged. Ticks were stimulated by gently exhalingin the vials. The efficacy of Compound 1 alone is shown in Table 23below. The synergistic efficacy of Compound 1 with amitraz is shown inTable 24. Within the same time period, the addition of amitraz to anequal dosage of compound 1 increased mean mortality. The EC50 and EC90values, and synergistic ratios of compound 1 and compound 1 with amitrazare shown in Table 25.

TABLE 23 Tick Efficacy of Compound 1 in DMSO Contact Test Rate is theppm of the solution used to treat the vials. 6 hour % Mortality 24 hour% Mortality 48 hour % Mortality Rate Avg. % Avg. % Avg. % Compound ppmRep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality 1 2580 60 70 90 100 95 100 100 100 6.25 10 10 10 50 100 75 70 100 85 1.6 0 00 30 40 35 30 40 35 0.4 0 0 0 30 0 15 30 0 15 0.1 0 0 0 0 0 0 0 0 00.025 0 0 0 0 0 0 0 0 0 0.006 0 0 0 0 0 0 0 0 0 0.0016 0 0 0 0 0 0 0 0 0Solvent 0 0 0 0 0 0 0 0 0 control Untreated 0 0 0 0 0 0 0 0 0 Control

TABLE 24 Synergistic Tick Efficacy of Compound 1 with Amitraz in DMSOContact Test. 6 hour Eval 24 hour Eval 48 hour Eval Rate Avg. % Avg. %Avg. % Compound ppm Rep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality Rep 1Rep 2 Mortality 1 + Amitraz 25 100 100 100 100 100 100 100 100 100 (12.5ppm) 6.25 100 100 100 100 100 100 100 100 100 1.6 50 50 50 100 100 100100 100 100 0.4 20 0 10 100 100 100 100 100 100 0.1 0 0 0 90 80 85 90 8085 0.025 0 0 0 40 70 55 40 70 55 0.006 0 0 0 20 40 30 20 40 30 0.0016 00 0 0 0 0 10 20 15 Amitraz 25 0 0 0 0 0 0 10 10 10 12.5 0 0 0 0 0 0 0 00 6.25 0 0 0 0 0 0 0 0 0 Solvent 0 0 0 0 0 0 0 0 0 control Untreated 0 00 0 0 0 0 0 0 Control Rate is the ppm of the solution used to treat thevials.

TABLE 25 EC50, EC90 and Synergistic Ratios of Tick Efficacy Formulationsof Compound 1 with Amitraz in DMSO Contact Test. 6 hour Eval 24 hourEval 48 hour Eval Compound EC50 EC90 EC50 EC90 EC50 EC90 1 17 >25 2.4916.6 2.17 9.71 1 + Amitraz 1.54 4.37 0.0184 0.149 0.0163 0.193 (12.5ppm) Synergistic 11 >5.72 135.3 111.4 133.1 50.3 Ratio for compound 1Synergistic ratio is EC50 or EC90 alone divided by EC50 or EC90 withAmitraz.

Formulations of compound 1 with lower concentrations of Amitraz alsoexhibited synergistic activity. Example 16 provides data showingunexpected and improved efficacy of compound 1 with low concentrationsof Amitraz. The EC90 values are substantially improved using compound 1.

Example 16 Tick Efficacy of Synergistic Formulations with ReducedDosages of Acaricide—Tick DMSO Contact Assay

The assay protocol was similar to the protocol of Example 15, with thefollowing exceptions: 1) The vials were visually evaluated at 4, 24 and48 hours post infestation for living/dead ticks and percent mortalitywas determined, and 2) the acaricide (amitraz) was added at dosages of12.5 ppm, 6.25 ppm, and 3.13 ppm.

The efficacy of Compound 1 alone is shown in Table 26 below. Thesynergistic efficacy of Compound 1 with different dosages of amitraz isshown in Table 27. Within the same time period, the addition of amitrazto an equal dosage of compound 1 increased mean mortality. The EC50 andEC90 values of compound 1 and compound 1 with different dosages ofamitraz are shown in Table 28, which clearly indicates superiorefficacy.

TABLE 26 Tick Efficacy of Compound 1 in DMSO Contact Test 4 hour %Mortality 24 hour % Mortality 48 hour % Mortality Rate Avg. % Avg. %Avg. % Compound ppm Rep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality Rep 1Rep 2 Mortality 1 25 90 70 80 100 100 100 100 100 100 6.25 40 70 55 100100 100 100 100 100 1.6 30 20 25 100 30 65 100 100 100 0.4 0 0 0 0 0 020 0 10 0.1 0 0 0 0 0 0 0 0 0 0.025 0 0 0 0 0 0 0 0 0 Solvent 0 0 0 0 00 0 0 0 control Untreated 0 0 0 0 0 0 0 0 0 Control Rate is the ppm ofthe solution used to treat the vials.

TABLE 27 Synergistic Tick Efficacy of Compound 1 with Different Dosagesof Amitraz in DMSO Contact Test. 4 hour % Mortality 24 hour % Mortality48 hour % Mortality Rate Avg. % Avg. % Avg. % Cmpd. ppm Rep 1 Rep 2Mortality Rep 1 Rep 2 Mortality Rep 1 Rep 2 Mortality 1 + Amitraz 25 10090 95 100 100 100 100 100 100 (12.5 ppm) 6.25 90 90 90 100 100 100 100100 100 1.6 60 50 55 100 100 100 100 100 100 0.4 0 0 0 100 100 100 100100 100 0.1 0 0 0 90 100 95 90 100 95 0.025 0 0 0 80 60 70 80 60 70 1 +Amitraz 25 90 100 95 100 100 100 100 100 100 (6.25 ppm) 6.25 80 90 85100 100 100 100 100 100 1.6 30 70 50 100 100 100 100 100 100 0.4 10 3020 100 100 100 100 100 100 0.1 0 10 5 100 100 100 100 100 100 0.025 0 00 80 80 80 80 80 80 1 + Amitraz 25 100 100 100 100 100 100 100 100 100(3.13 ppm) 6.25 100 100 100 100 100 100 100 100 100 1.6 40 70 55 100 100100 100 100 100 0.4 0 10 5 100 100 100 100 100 100 0.1 0 0 0 100 100 100100 100 100 0.025 0 0 0 80 50 65 80 80 80 Amitraz 12.5 0 0 0 0 0 0 0 0 06.25 0 0 0 0 0 0 0 0 0 3.13 0 0 0 0 0 0 0 0 0 Rate is the ppm of thesolution used to treat the vials.

TABLE 28 EC50, EC90 and Synergistic Ratios of Tick Efficacy Formulationsof Compound 1 with Different Dosages of Amitraz in DMSO Contact Test. 4hour Eval 24 hour Eval 48 hour Eval Compound EC50 EC90 EC50 EC90 EC50EC90 1 5.42 >25 1.54 1.75 0.45 0.51 1 + Amitraz 1.51 4.13 <0.025 0.06<0.025 0.06 (12.5 ppm) 1 + Amitraz 1.50 10.78 <0.025 0.026 <0.025 0.026(6.25 ppm) 1 + Amitraz 1.47 3.45 <0.025 0.03 <0.025 0.026 (3.13 ppm)Synergistic ratios 1 + Amitraz 3.59 >6.05 >61.6 29.2 >18 8.5 (12.5 ppm)1 + Amitraz 3.61 >2.3 >61.6 67.3 >18 19.6 (6.25 ppm) 1 + Amitraz3.69 >7.25 >61.6 58.3 >18 19.6 (3.13 ppm) Synergistic ratio is EC50 orEC90 alone divided by EC50 or EC90 with Amitraz.

Example 17 Formulations for Dual Cavity Container

One means for topically delivering the inventive combination of activeingredients such as those described in Examples above is to utilize adual cavity container.

In one embodiment of the use of a dual cavity container, the firstcavity of the dual-cavity container contains a clear colorless/lightyellow composition comprising of amitraz and octyl benzoate as asolvent.

Ingredients Function % Amitraz Active 20.0 w/v Octyl benzoate Solventq.s. 100

This composition may also comprise 2,4-dimethylaniline,formamidine-2′,4′-xylidide, N-methyl-N′-(2,4-xylyl)formamidine, and/orN,N′-bis(2,4-xylyl)formamidine; for example, in amounts ranging fromabout 0.1% to about 8% of the 20% w/v. In one embodiment of thiscomposition, water may be present; for example, in an amount of up toabout 0.06% w/w. In another embodiment of this composition, water may bepresent, for example, in an amount of up to about 0.4% w/w. Thecomposition may also have a maximum acid value of about 0.14.

In the second cavity of the dual-cavity container is a clear ambercomposition comprising fipronil and s-methoprene

Ingredients Function % Fipronil Active 10.0 w/v s-Methoprene Active  9.0w/v Solvent Solvent q.s. 100

This composition may also include the antioxidants BHA and BHT. Theamount of BHA if present ranges from 0.016-0.022% w/v and the amount forBHT if present ranges from 0.008-0.011% w/v. In one embodiment of thiscomposition, water may be present in an amount of up to 1.5% w/w. Inanother embodiment of this composition, water may be present in anamount of up to 10% w/w.

In another embodiment of the use of a dual cavity container, the firstcavity of the dual-cavity container contains a clear colorless/lightyellow composition comprising of amitraz and octyl benzoate as asolvent.

Ingredients Function % Amitraz Active 20.0 w/v Octyl benzoate Solventq.s. 100

This composition may also comprise 2,4-dimethylaniline,formamidine-2′,4′-xylidide, N-methyl-N′-(2,4-xylyl)formamidine, and/orN,N′-bis(2,4-xylyl)formamidine; for example, in amounts ranging fromabout 0.1% to about 8% of the 20% w/v. In one embodiment of thiscomposition, water may be present; for example, in an amount of up toabout 0.06% w/w. In another embodiment of this composition, water may bepresent, for example, in an amount of up to about 0.4% w/w. Thecomposition may also have a maximum acid value of about 0.14.

In the second cavity of the dual-cavity container is a clear ambercomposition comprising fipronil and s-methoprene

Ingredients Function % Fipronil Active  9.8 w/w s-Methoprene Active 8.82w/w Solvent Solvent q.s. 100

This composition may also include the antioxidants BHA and BHT. Theamount of BHA if present ranges from 0.001-0.03% w/v and the amount forBHT if present ranges from 0.002-0.018% w/v. In one embodiment of thiscomposition, water may be present in an amount of up to 1.5% w/w. Inanother embodiment of this composition, water may be present in anamount of up to 10% w/w.

The invention is further described by the following numbered paragraphs:

-   1. A veterinary formulation for treating or preventing a parasitic    infestation in an animal comprising:-   (a) a 1-aryl-5-alkyl or 5-haloalkylpyrazole of formula (IA) or a    veterinarily acceptable salt thereof,

wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl, ethyl or C₁-C₄ haloalkyl;

R_(4a) is halogen;

R_(6a) is C₁-C₄ alkyl or haloalkyl;

R_(13a) is halogen;

R_(11a) is C₁-C₄ haloalkyl; and

m is 0, 1 or 2;

-   (b) a veterinarily acceptable carrier; and-   (c) optionally a crystallization inhibitor.-   2. A composition for the treatment or prevention of a parasitic    infestation in an animal comprising at least one 1-arylpyrazole    compound in a first veterinarily acceptable carrier, at least one    formamidine compound in a second veterinarily acceptable carrier,    and optionally at least one crystallization inhibitor(s), wherein    the 1-arylpyrazole compound(s) and first veterinarily acceptable    carrier are isolated and not in fluid communication with the    formamidine compound(s) and the second veterinarily acceptable    carrier.-   3. The composition of paragraph 2, wherein the one or more    1-arylpyrazole compound(s) and the first veterinarily acceptable    carrier are in one cavity of a dual-cavity container and the one or    more formamidine compound(s) and the second veterinarily acceptable    carrier are in a second cavity of a dual-cavity container, wherein    the first cavity is defined by a front wall and a divider wall; and    the second cavity is defined by a rear wall and the divider wall.-   4. The composition of paragraph 2 or 3, wherein the at least one    1-arylpyrazole compounds has    formula (IB):

wherein:

-   R_(1b) is alkyl, CN or halogen;-   R_(2b) is S(O)_(n)R_(14b) or 4,5-dicyanoimidazol-2-yl or haloalkyl;-   R_(14b) is alkyl or haloalkyl;

R_(3b) is a hydrogen, halogen, —NR_(7b)R_(8b), —S(O)_(m)R_(9b),—C(O)R_(9b), —C(O)OR_(9b), alkyl, haloalkyl, —OR_(10b) or an—N═C(R_(11b))(R_(12b));

-   R_(6b) is a halogen, haloalkyl, haloalkoxy, S(O)_(q)CF₃ or SF₅    group;-   R_(7B) and R_(8B) independently represent a hydrogen, alkyl,    haloalkyl, —C(O)alkyl, —S(O)_(r)CF₃, acyl or alkoxycarbonyl; or-   R_(7b) and R_(8b) can together form a divalent alkylene radical    which is optionally interrupted by one or two divalent heteroatoms;-   R_(9b) is an alkyl or haloalkyl;-   R_(10b) is hydrogen, alkyl or haloalkyl;-   R_(11b) is hydrogen or alkyl radical;-   R_(12b) is an optionally substituted aryl or an optionally    substituted heteroaryl group;-   R_(4b) and R_(13b) represent, independently of one another,    hydrogen, halogen CN or NO₂;-   m, n, q and r represent, independently of one another, an integer    equal to 0, 1 or 2; and-   Z represents a trivalent nitrogen atom or a C—R_(13b) radical, the    three other valencies of the carbon atom forming part of the    aromatic ring.-   5. The composition of paragraph 4, wherein:    -   R_(1b) is methyl, CN or halogen;    -   R_(2b) is S(O)_(n)R_(14b);    -   R_(14b) is C₁-C₆-alkyl or C₁-C₆-haloalkyl;    -   R_(3b) is —NR_(7b)R_(8b),    -   R_(7b) and R_(8b) independently represent a hydrogen,        C₁-C₆-alkyl, C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl, —S(O)_(r)CF₃,        C₁-C₆-acyl or C₁-C₆-alkoxycarbonyl radical;    -   R_(6b) is a halogen, C₁-C₆-haloalkyl, or C₁-C₆-haloalkoxy;    -   m, n, q and r represent, independently of one another, an        integer equal to 0 or 1; and    -   Z is a C—R_(13b) radical.-   6. The composition of paragraph 4, wherein:

R_(1b) is methyl, CN or halogen;

R_(2b) is S(O)_(n)R_(14b);

R_(14b) is C₁-C₆-alkyl or C₁-C₆-haloalkyl;

R_(3b) is alkyl or haloalkyl;

R_(6b) is a halogen, C₁-C₆-haloalkyl, or C₁-C₆-haloalkoxy;

m, n, q and r represent, independently of one another, an integer equalto 0 or 1; and

Z is a C—R_(13b) radical.

-   7. The composition of paragraph 2, wherein the first veterinarily    acceptable carrier comprises acetone, acetonitrile, benzyl alcohol,    ethanol, isopropanol, diisobutyl adipate, diisopropyl adipate, butyl    diglycol, dipropylene glycol n-butyl ether, ethylene glycol    monoethyl ether, ethylene glycol monomethyl ether, dipropylene    glycol monomethyl ether, liquid polyoxyethylene glycols, propylene    glycol monomethyl ether, propylene glycol monoethyl ether,    2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl    ether, triacetin, butyl acetate, octyl acetate, propylene carbonate,    butylene carbonate, dimethyl sulfoxide, an amide, dimethylformamide,    dimethylacetamide, or any combination thereof.-   8. The composition of paragraph 2, wherein the second veterinarily    acceptable carrier comprises aryl ethers, alkoxybenzene compounds;    aliphatic carboxylic acid esters, aromatic carboxylic acid esters,    aliphatic ketones, cyclic ketones, or mixtures thereof.-   9. The composition of paragraph 2, wherein the second veterinarily    acceptable carrier comprises methoxybenzene, butyl acetate, benzyl    acetate, methyl isobutyl ketone, ethyl benzoate, benzyl benzoate,    octyl acetate, or mixtures thereof.-   10. The composition of paragraph 2, wherein the second veterinarily    acceptable carrier comprises an aprotic solvent with a dielectric    constant of about 2 to about 30.-   11. A composition for the treatment and prevention of a parasitic    infestation in an animal comprising at least one formamidine    compound(s), at least one 1-arylpyrazole compound(s) of formula    (IA), or veterinarily acceptable salts thereof,

wherein:

R_(2a) is —S(O)_(m)R_(11a);

R_(3a) is methyl, ethyl or C₁-C₄ haloalkyl;

R_(4a) is halogen;

R_(6a) is C₁-C₄ alkyl or haloalkyl;

R_(13a) is halogen;

R_(11a) is C₁-C₄ haloalkyl; and

m is 0, 1 or 2;

at least one veterinarily acceptable carriers; and

optionally a crystallization inhibitor.

-   12. The composition of paragraph 2 or 11, wherein the at least one    formamidine compound has the formula (II):

wherein:

x is an integer from 0-5;

R₁₄ is alkyl, halogen or —OC(═O)NR_(a)R_(b),

wherein R_(a) and R_(b) are independently hydrogen or alkyl;

R₁₅ is hydrogen or alkyl;

R₁₆ is hydrogen or alkyl; and

R₁₇ is hydrogen, alkyl or

-   13. The composition of paragraph 2 or 11, wherein the at least one    formamidine compound comprises amitraz, formetanate, chloromebuform,    formparanate or chlodimeform.-   14. The composition of paragraph 2 or 11, wherein the at least one    1-arylpyrazole compound(s) is combined with a first veterinarily    acceptable carrier and the at least one formamidine compounds is    combined with a second veterinarily acceptable carrier; and wherein    the 1-arylpyrazole compound(s) and the first veterinarily acceptable    carrier are compartmentalized together and not in fluid    communication with, the at least one formamidine compound(s) and the    second veterinarily acceptable carrier.-   15. A composition for the treatment and prevention of a parasitic    infestation in an animal comprising at least one formamidine    compound and at least one aprotic solvent(s) with a dielectric    constant of about 2 to about 30, wherein the composition is stable    for at least 24 months at 25° C.-   16. The composition of paragraph 15, wherein the at least one    formamidine compound is amitraz.-   17. The composition of paragraph 15, wherein the aprotic solvent(s)    with a dielectric constant of about 2 to about 30 has a water    content of less than about 0.05% (w/w).-   18. The composition of paragraph 15, wherein the at least one    aprotic solvent(s) with a dielectric constant of about 2 to about 30    is a C₁-C₁₀ carboxylic acid ester, a phenyl carboxylic acid ester, a    carboxylic acid benzyl ester, a benzoic acid C₁-C₄ alkyl ester, a    C₁-C₆ saturated aliphatic ketone, or a mixture thereof.-   19. The composition of paragraph 15, comprising two or more aprotic    solvents with a dielectric constant of about 2 to about 30, wherein    a dissipation of an unpleasant odor from the composition occurs    within about 5 minutes to within about 25 minutes after application.-   20. A method for the treatment or prevention of a parasitic    infestation in an animal comprising administering an effective    amount of the composition of paragraph 2 or 11 to the animal in need    thereof.-   21. The method of paragraph 20, wherein the at least one    1-arylpyrazole compound is fipronil.-   22. The method of paragraph 20, wherein the at least one formamidine    compound is amitraz.-   23. The method of paragraph 20, wherein the composition is    administered using a dual-cavity container, wherein the    1-arylpyrazole compound(s) and the first veterinarily acceptable    carrier are administered from a first cavity of the dual cavity    container and the formamidine compound(s) and the second    veterinarily acceptable carrier are administered from a second    cavity of the dual cavity container.-   24. The method of paragraph 22, wherein the 1-arylpyrazole    compound(s) and the formamidine compound(s) are administered    simultaneously.-   25. A method for the treatment or prevention of a parasitic    infestation in an animal comprising administering an effective    amount of the composition of paragraph 11 to the animal in need    thereof.-   26. The method of paragraph 25, wherein the at least one    1-arylpyrazole compound(s) is in a first veterinarily acceptable    carrier, and the at least one formamidine compound(s) is in a second    veterinarily acceptable carrier; wherein the 1-arylpyrazole    compound(s) and first veterinarily acceptable carrier are    compartmentalized together and not in fluid communication with, the    formamidine compound(s) and the second veterinarily acceptable    carrier.-   27. The method of paragraph 26, wherein the 1-arylpyrazole    compound(s) and the formamidine compound(s) are administered    simultaneously.-   28. The method of paragraph 25, wherein the at least one formamidine    compound is amitraz.-   29. A method for the treatment or prevention of a parasitic    infestation in an animal comprising administering to the animal an    effective amount of a composition comprising at least one    1-arylpyrazole compound in a first veterinarily acceptable carrier    and at least one formamidine compound in a second veterinarily    acceptable carrier from a dual-cavity container; wherein the at    least one 1-arylpyrazole compound(s) and the first veterinarily    acceptable carrier are in one cavity of the dual-cavity container    and the at least one formamidine compound and the second    veterinarily acceptable carrier is in a second cavity of the    dual-cavity container; and wherein the first cavity is defined by a    front wall and a divider wall; and the second cavity is defined by a    rear wall and the divider wall.-   30. The method of paragraph 29, wherein the at least one    1-arylpyrazole compound is fipronil.-   31. The method of paragraph 29, wherein the at least one formamidine    compound(s) is amitraz.-   32. The method of paragraph 29, wherein the 1-arylpyrazole    compound(s) and the formamidine compound(s) are administered    simultaneously.-   33. A kit for the treatment or prevention of a parasitic infestation    in an animal, comprising: at least one 1-arylpyrazole compound in a    first veterinarily acceptable carrier, at least one formamidine    compound in a second veterinarily acceptable carrier, and a multiple    cavity container; wherein the at least one 1-arylpyrazole    compound(s) in a first veterinarily acceptable carrier is in a first    cavity of the multiple cavity container and the at least one    formamidine compound(s) in a second veterinarily acceptable carrier    is in a second cavity of the multiple cavity container; and wherein    the first cavity is defined by a front wall and a divider wall; and    the second cavity defined by a rear wall and the divider wall.

Having thus described in detail various embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

What is claimed is:
 1. A kit for the treatment or prevention of aparasitic infestation in an animal, comprising: (i) at least one1-arylpyrazole compound of formula (IB) in a first veterinarilyacceptable carrier:

wherein: R_(1b) is alkyl, CN or halogen; R_(2b) is S(O)_(n)R_(14b) or4,5-dicyanoimidazol-2-yl or haloalkyl; R_(14b) is alkyl or haloalkyl;R_(3b) is a hydrogen, halogen, —NR_(7b)R_(8b), —S(O)_(m)R_(9b),—C(O)R_(9b), —C(O)OR_(9b), alkyl, haloalkyl, —OR_(10b) or an—N═C(R_(11b))(R_(12b)); R_(6b) is a halogen, haloalkyl, haloalkoxy,S(O)_(q)CF₃ or SF₅ group; R_(7b) and R_(8b) independently represent ahydrogen, alkyl, haloalkyl, —C(O)alkyl, —S(O)_(r)CF₃, acyl oralkoxycarbonyl; or R_(7b) and R_(8b) can together form a divalentalkylene radical which is optionally interrupted by one or two divalentheteroatoms; R_(9b) is an alkyl or haloalkyl; R_(10b) is hydrogen, alkylor haloalkyl; R_(11b) is hydrogen or alkyl radical; R_(12b) is anoptionally substituted aryl or an optionally substituted heteroarylgroup; R_(4b) and R_(13b) represent, independently of one another,hydrogen, halogen CN or NO₂; m, n, q and r represent, independently ofone another, an integer equal to 0, 1 or 2; and Z represents a trivalentnitrogen atom or a C—R_(13b) radical, the three other valencies of thecarbon atom forming part of the aromatic ring; (ii) at least oneformamidine compound of formula (II) in a second veterinarily acceptablecarrier:

wherein: x is an integer from 0-5; R₁₄ is alkyl, halogen or—OC(═O)NR^(a)R_(b), wherein R_(a) and R_(b) are independently hydrogenor alkyl; R₁₅ is hydrogen or alkyl; R₁₆ is hydrogen or alkyl; and R₁₇ ishydrogen, alkyl or

and (iii) a dual-cavity container; wherein the dual-cavity containercomprises a front wall, a divider wall, a rear wall and an openingmechanism at one end of the container; the first cavity of thedual-cavity container is defined by the front wall and the divider wall;the second cavity of the dual-cavity container is defined by the rearwall and the divider wall; and wherein the front wall, the divider walland the rear wall are coupled along part of their perimeter to definethe two cavities; the 1-arylpyrazole compound(s) of formula (IB) in thefirst veterinarily acceptable carrier is in the first cavity of thedual-cavity container and the formamidine compound(s) of formula (II) inthe second veterinarily acceptable carrier is in the second cavity ofthe dual-cavity container; and wherein the 1-arylpyrazole compound(s) offormula (IB) in the first veterinarily acceptable carrier and theformamidine compound(s) of formula (II) in the second veterinarilyacceptable carrier are not in fluid communication.
 2. The kit of claim1, wherein the first veterinarily acceptable carrier comprises C1-C10alcohols or esters thereof, C10-C18 saturated fatty acids or estersthereof, C10-C18 monounsaturated fatty acids or esters thereof,monoesters or diesters of aliphatic diacids, glycerol monoesters,glycerol diesters, glycerol triesters, glycols, glycol ethers, glycolesters, glycol carbonates; or polyethylene glycols, or monoethers,diethers, monoesters or diesters thereof; or a combination thereof. 3.The kit of claim 2, wherein the first veterinarily acceptable carriercomprises a C1-C10 alcohol, a glycol ether, a polyethylene glycolmonoether or a polyethylene glycol diether, or a mixture thereof.
 4. Thekit of claim 1, wherein the first veterinarily acceptable carriercomprises acetone, acetonitrile, benzyl alcohol, ethanol, isopropanol,diisobutyl adipate, diisopropyl adipate, butyl diglycol, dipropyleneglycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycolmonomethyl ether, dipropylene glycol monomethyl ether, liquidpolyoxyethylene glycols, propylene glycol monomethyl ether, propyleneglycol monoethyl ether, 2-pyrrolidone, N-methylpyrrolidone, diethyleneglycol monoethyl ether, triacetin, butyl acetate, octyl acetate,propylene carbonate, butylene carbonate, dimethyl sulfoxide,dimethylformamide or dimethylacetamide, or any combination thereof. 5.The kit of claim 1, wherein the second veterinarily acceptable carriercomprises aryl ethers, alkoxybenzene compounds, aliphatic carboxylicacid esters, aromatic carboxylic acid esters, aliphatic ketones orcyclic ketones, or mixtures thereof.
 6. The kit of claim 1, wherein thesecond veterinarily acceptable carrier comprises methoxybenzene, butylacetate, benzyl acetate, methyl isobutyl ketone, ethyl benzoate, benzylbenzoate or octyl acetate, or mixtures thereof.
 7. The kit of claim 1,wherein the first veterinarily acceptable carrier further comprisesabout 1% to about 20% (w/v) of a crystallization inhibitor selected fromanionic surfactants, cationic surfactants, an amine salt, non-ionicsurfactants, amphoteric surfactants, polyvinylpyrrolidone, polyvinylalcohols, copolymers of vinyl acetate and of vinylpyrrolidone,N-methylpyrrolidone, dimethylsufoxide, polyethylene glycols, benzylalcohol, mannitol, glycerol, sorbitol, polyoxyethylenated esters ofsorbitan, lecithin, sodium carboxymethylcellulose and polymers derivedfrom acrylic monomers, or a mixture thereof.
 8. The kit of claim 7,wherein the crystallization inhibitor comprises polyvinylpyrrolidone, acopolymer of vinyl acetate and vinylpyrrolidone, a polyethylene glycolor a non-ionic surfactant, or a combination thereof.
 9. The kit of claim7, wherein the non-ionic surfactant is a polyoxyethylenated ester ofsorbitan, a polyoxyethylenated alkyl ether, polyethylene glycolstearate, a polyoxyethylenated derivative of castor oil, a polyglycerolester, a polyoxyethylenated fatty alcohol, a polyoxyethylenated fattyacid or a copolymer of ethylene oxide and propylene oxide.
 10. The kitof claim 1, wherein the composition further comprises about 0.01 toabout 0.05% (w/v) of an antioxidant.
 11. The kit of claim 10, whereinthe antioxidant is butylated hydroxyanisole, butylated hydroxytoluene,ascorbic acid, sodium metabisulphite, propyl gallate or sodiumthiosulfate or a mixture thereof.
 12. The kit of claim 1, wherein the1-arylpyrazole compound is fipronil.
 13. The kit of claim 1, wherein theformamidine compound is amitraz.
 14. The kit of claim 12, whereinfipronil is present at a concentration of about 5% (w/v) to about 15%(w/v).
 15. The kit of claim 13, wherein amitraz is present at aconcentration of about 1% (w/v) to about 30% (w/v).
 16. The kit of claim1, wherein the 1-arylpyrazole compound is fipronil; the formamidinecompound is amitraz; and wherein fipronil is present in the firstveterinarily acceptable carrier at a concentration of about 5% (w/v) toabout 15% (w/v) and amitraz is present in the second veterinarilyacceptable carrier at a concentration of about 5% (w/v) to about 20%(w/v).
 17. The kit of claim 16, wherein the first veterinarilyacceptable carrier comprises ethanol, isopropanol, diethyleneglycolmonoethyl ether, N-methylpyrrolidone, or a mixture thereof; and thesecond veterinarily acceptable carrier comprises methoxybenzene, butylacetate, benzyl acetate, ethyl benzoate, benzyl benzoate or octylacetate, or a mixture thereof.
 18. The kit of claim 17, wherein thesecond veterinarily acceptable carrier comprises octyl acetate.
 19. Thekit of claim 17, wherein the first veterinarily acceptable carrierfurther comprises about 1% to about 20% (w/v) of a crystallizationinhibitor selected from non-ionic surfactants, polyvinylpyrrolidone,polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone,polyethylene glycols, mannitol, sorbitol, polyoxyethylenated esters ofsorbitan, or a mixture thereof.
 20. The kit of claim 19, wherein thepolyoxyethylenated ester of sorbitan is polysorbate
 80. 21. The kit ofclaim 20, wherein the crystallization inhibitor is a mixture ofpolyvinylpyrrolidone and a polysorbate
 80. 22. The kit of claim 1,wherein the first veterinarily acceptable carrier or the secondveterinarily acceptable carrier further comprises an additionalparasiticidal active agent.
 23. The kit of claim 22, wherein theadditional parasiticidal active agent is an avermectin or milbemycincompound, an insect growth regulator, a pyrethroid, a benzimidazole, animidazothiazole, praziquantel, an isoxazoline compound, an aminoacetonitrile compound or an aryloazol-2-yl cyanoethylamino compound. 24.The kit of claim 23, wherein the insect growth regulator is methoprene,pyriproxyfen, hydroprene, cyromazine, fluazuron, lufenuron or novaluron.25. The kit of claim 23, wherein the avermectin or milbemycin compoundis abamectin, dimadectin, doramectin, emamectin, eprinomectin,ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycinD, moxidectin, nemadectin or milbemycin oxime.
 26. The kit of claim 1,wherein the divider wall has a thickness of about 10% to about 40% ofeither the front wall or the rear wall.
 27. The kit of claim 1, whereinthe divider wall has a thickness of about 30% to about 70% of either thefront wall or the rear wall.
 28. The kit of claim 1, wherein the dividerwall has a thickness of about 40% to about 60% of either the front wallor the rear wall.
 29. The kit of claim 1, wherein the divider wallcomprises a barrier film selected from a flexible monolayer film or alaminate flexible film.
 30. The kit of claim 29, wherein the dividerwall comprises a material selected from the group consisting ofpolyester, polypropylene, polyethylene, ethyl vinyl alcohol, ethyl vinylacetate, polyamide, poly acrylonitrile, fluoropolymer, polychlorotrifluoroethylene and aluminium foil.
 31. The kit of claim 1,wherein the front wall and the rear wall comprise a film selected from arigid monolayer film or a laminate rigid film.
 32. The kit of claim 31,wherein the front wall and the rear wall comprise a material selectedfrom the group consisting of polyethylene terephthalate, amorphouspolyethylene terephthalate, polyethylene terephthalate glycol,crystalline polyethylene terephthalate, polyvinyl chloride,polypropylene, polyethylene, polyamide, cycloolefin copolymers, polyacrylonitrile, fluoropolymer and poly chlorotrifluoroethylene.
 33. Thekit of claim 1, wherein the opening mechanism comprises a fracture line,a die cut or a perforation, or a combination thereof, at one end of thecontainer.
 34. The kit of claim 33, wherein the opening mechanism is adie cut.
 35. The kit of claim 33, wherein the opening mechanismcomprises two half-moon shaped die cuts adjacent to a fracture line. 36.The kit of claim 1, wherein the first and second cavities are formed bya thermoforming process.
 37. The kit of claim 1, wherein the dividerwall is constructed from a central ribbon and the front and rear wallsare constructed from an external ribbon.
 38. The kit of claim 1, whereinthe front wall, the divider wall and the back wall are coupled alongpart of their perimeter to define the two cavities by bonding or weldingthem together.
 39. The kit of claim 1, wherein in the compound offormula (IB): R_(1b) is CN; R_(2b) is S(O)_(n)R_(14b); R_(14b) ishaloalkyl; R_(3b) is —NR_(7b)R_(8b) or alkyl; R_(6b) is haloalkyl;R_(7b) and R_(8b) are each independently hydrogen or alkyl; R_(4b) andR_(13b) are independently halogen; and Z is C—R_(13b).
 40. The kit ofclaim 1, wherein in the compound of formula (II): x is 1 or 2; R₁₄ isC₁-C₄-alkyl, chloro or —OC(═O)NR_(a)R_(b) where R_(a) and R_(b) areindependently hydrogen or C₁-C₄-alkyl; R₁₅ is hydrogen; R₁₆ isC₁-C₄-alkyl; and R₁₇ is C₁-C₄-alkyl or